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U.S. Department Of Health And Human Services Public Health Service Agency For Toxic Substances And Disease Registry

National Exposure Registry Benzene Subregistry Baseline Through Followup 4 Technical Report February 2001

This report was supported in full by funds from the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) trust fund through the Agency for Toxic Substances and Disease Registry, U.S. Department of Health and Human Services.

DISCLAIMER

The use of company or product names is for identification only and does not constitute endorsement by the Agency for Toxic Substances and Disease Registry or the U.S. Department of Health and Human Services.

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DISCLAIMER

EXECUTIVE SUMMARY

This is a report on the baseline activities and results of the statistical analyses of the Baseline through Followup 4 data for the Benzene Subregistry of the National Exposure Registry (NER). The NER was created in response to the congressional mandate contained in the 1980 Comprehensive Environmental Response, Compensation, and Liability Act and reiterated in the Superfund Amendments and Reauthorization Act of 1986. This mandate directed the Agency for Toxic Substances and Disease Registry (ATSDR) to create a registry of people exposed to hazardous substances in the environment. The Benzene Subregistry is one of four existing chemical-specific subregistries in the NER.

As with the other subregistries in the NER, the Benzene Subregistry is a database on people who have been exposed to a specific chemical, in this case benzene. The purpose of the Subregistry is to assess the long-term health consequences, if any, of long-term past exposures to low levels of benzene in drinking water. The Subregistry itself is not a definitive study; cause-effect relationships cannot be established using only Subregistry-based information. However, the Subregistry will furnish the information needed to generate appropriate and valid hypotheses for future activities, such as epidemiologic studies.

The data collected for each member of the Benzene Subregistry include environmental data, demographic information, smoking and occupational histories, and self-reported responses to 25 general health status questions. The data files for each Subregistry are established at the time baseline data are collected. Followup surveys are conducted at the end of the first and second years, then at 2-year intervals, thereafter, to update the data files.

The Benzene Subregistry contains information on 1,143 persons (1,127 living and 16 deceased at the time of baseline data collection) who had documented exposure to benzene in their drinking water and were exposed for at least 30 days. These individuals had resided in Texas. The participation rate for those eligible was 97%.

Reported health outcome rates were calculated for the Benzene Subregistrants and compared with morbidity data from the 1990 National Health Interview Survey (NHIS). When interpreting the statistical results and planning future activities based on these results, the limitations of the Subregistry data files must be kept in mind. For instance, a bias in the rate of reporting could have existed because people were aware of their benzene exposure, had been advised of the potential effect on their health, and might have sought medical care more often than the general population. To moderate this potential bias, the Subregistry data were collected with the restriction that a health care provider must have told persons that they had the condition or have treated them for it. Also, some of the questions in the two surveys were worded differently, making direct comparisons of the reported rates more difficult to interpret. Given the large number of comparisons used in the analyses, there might be some false positive findings. These limitations and restrictions are discussed in this report.

The morbidity data analyses indicated an increased reporting of several health outcomes by Benzene Subregistry registrants. Statistically significant increases (p £ 0.01 significance level) at specific interview periods were observed for anemia and other blood disorders at Baseline through Followup 4; arthritis, rheumatism, and other joint disorders at Followup 1; cancer at Baseline through Followup 3; diabetes at Followup 3; kidney disease at Baseline; liver problems at Followups 1 and 2; respiratory allergies and other problems, such as hay fever at Baseline through Followup 4; skin rashes, eczema, or other skin allergies and Baseline and Followups 1,3, and 4; stroke at Followups 1 through 4; ulcers, gallbladder trouble, or stomach or intestinal problems at Followups 1 and 3; and urinary tract disorders, including prostate trouble, at Baseline through Followup 4. Statistically significant deficits were reported for the Benzene Subregistry population for the following health conditions at various interview periods: hearing and speech impairments, asthma and emphysema, and arthritis. The rates of these conditions might have been affected by the limitation imposed on registrants' reporting, that is, that a health care provider had told them they had the condition or had treated them for it. This limitation was not part of the NHIS.

The findings in this report cannot be used to identify a causal relationship between the health outcomes and benzene exposure. Additionally, some methodological differences in data collection may have biased the reporting rates, resulting in false positive findings. The findings of this report do, however, reinforce the need to continue regular follow-up of this population.

Keeping registrants informed of all current information related to their exposures is another of the stated goals of the NER. Both a registrant report and a one-page fact sheet, written for the general public and containing the findings of this technical report, were prepared and sent to each registrant, and then released to the media. The mailing was followed by a public availability meeting at the site for discussion.

SECTION 1: INTRODUCTION

This is a report on the activities and findings from the analyses of data collected from registrants of the Benzene Subregistry at five (5) time points: Baseline and Followups 1-4. The Benzene Subregistry is part of the National Exposure Registry (NER), which was created and is being maintained by the Agency for Toxic Substance and Disease Registry (ATSDR).

In 1988, the policies and procedures proposed for the NER were reviewed extensively by several committees composed of independent scientists, state representatives, representatives of other federal agencies, and other interested people. The revised policies and procedures were published in the NER Policies and Procedures Manual (1). The Benzene Subregistry was one of the first Subregistries established as part of the NER program. The NER currently contains four chemical-specific Subregistries (trichloroethylene [TCE], trichloroethane [TCA], dioxin, and benzene).

The goals and objectives of the Benzene Subregistry reflect those of the NER; specifically, it will be used to facilitate epidemiologic or health studies and surveillance, and will provide information that can be used to assess the effects of exposure to benzene on a general population. Additionally, the Benzene Subregistry will enable federal, state, and local officials to provide exposed persons with timely, relevant information about benzene exposure, potential adverse effects related to that exposure, preventive measures, or therapeutic advances that were not understood when the Benzene Subregistry was established.

The Policies and Procedures Manual (1) describes all policies, procedures, and operational details pertinent to establishing the Benzene and other Subregistries of the NER. Specific topics from the policies and procedures document are reiterated in this report, where necessary, for clarity.

The objective of this report is to present the results of the statistical analyses comparing the reporting rates of registrants at various time points for specific health outcomes with national rates from the National Health Interview Survey (NHIS). The report is an update on the latest Benzene Subregistry findings and highlights some health outcomes and predictive variables to consider for analysis during future epidemiologic or health studies. Results from the analyses presented in this report can be used to suggest specific hypotheses for future research on the Benzene Subregistry population and potentially other residential populations that have experienced similar exposures to benzene.

Section 2 of the report reviews the rationale for the selection of benzene as a primary contaminant for the NER and describes in details the site meeting the criteria for inclusion in the Benzene Subregistry. Section 2 also provides information on the environmental data and periods of exposure. A discussion of the data collection periods, participation rates, and number of registrants is included.

Section 3 describes the methods used for data analysis. It provides details for the descriptive and statistical comparison of the Benzene Subregistry data with national survey data files for smoking habits and demographic characteristics and reported rates of adverse health outcomes. Section 4 provides an overview of the characteristics and health status of registrants who took part in each of the data collection efforts and the results of the descriptive comparisons between the Benzene Subregistry data and the NHIS data. Section 5 contains the results of the health outcome reporting rate comparisons between the Benzene Subregistry at all five time points (Baseline through Followup 4) and the NHIS. Section 6 summarizes the findings of the report and discusses them in relationship to the published literature. Section 7 states the conclusions of the analysis of the Benzene Subregistry data and outlines future activities related to the Subregistry.

SECTION 2: BACKGROUND OF THE BENZENE SUBREGISTRY

SELECTION OF BENZENE AS A PRIMARY CONTAMINANT

In 1989, benzene was selected as the primary chemical for a Subregistry of the NER (1,2). This report also provides details on the presence of benzene in the environment, as well as a summary of evidence of adverse effects observed in both human and animal studies. In summary, the factors that led to the selection of benzene included the prioritization of benzene on the Hazardous Substance Priority List (3); ubiquitousness of benzene in the environment; published evidence of benzene toxicity in workers and in toxicologic studies; and the paucity of information on low-level, long-term exposures to benzene. Each of these factors suggested that establishing of a Benzene Subregistry could contribute significantly to the detection of adverse human health effects, should they exist, following long-term, low-level exposure to benzene in the environment.

SELECTION AND DESCRIPTION OF BENZENE SITE

The site selection process used to develop subregistries for the NER is described in the Policies and Procedures Manual (1). Selection of the Three Lakes Municipal Utilities District (TLMUD) as the site for the Benzene Subregistry has been previously described (4).

The criteria for selection included documentation of exposure levels and duration, identification and estimated size of the exposed population, identification of susceptible subpopulations, and identification of the number and levels of secondary contaminants (1,5). Although 263 potential sites were identified as having benzene as a contaminant of drinking water, only one site was eligible for inclusion in the Benzene Subregistry.

The TLMUD (Figure 2-1) is a small municipality in Harris County, Texas on Highway 249 (the Tomball Parkway), between Houston and Tomball. The TLMUD received its drinking water from a well located near the community. Benzene was first discovered in the TLMUD water supply in September 1990. The contaminated well was the only well serving the TLMUD and water was not treated before it entered the distribution system. The TLMUD is composed of two subdivisions, Three Lakes and Three Lakes Village, with approximately 1,200 residents. Because the site used a public water system, and because water samples were taken from the end of the distribution system, for the purpose of this report exposures for all registrants were considered to be the same. The duration of exposure considered by the Registry is from January 1, 1979, through October 1990, which represents documented beginning dates and confirmed ending dates of use of contaminated water (see Table 2-1). See Table 2-2 for a complete list of contaminants found in the TLMUD water supply.

DATA COLLECTION

Registrants were identified using three key components to define individual eligibility and exposure: (1) valid information indicated the presence of the contaminant(s) of interest in one or more of the media of interest; (2) evidence, for a given individual, of an appropriate route(s) of exposure;

Figure 2-1.—Location of Three Lakes Municipal Utilities District, Texas.

Table 2-1.—Summary of environmental data.

Benzene Subregistry Site	Year Exposure Began	Exposure Period* (Number of Years)	Maximum Level of Benzene Reported (ppb)†
Three Lakes Municipal	1979	11.75	66.0

*Exposure period is based on best available evidence of when contamination occurred and when exposure ceased following switch to an alternative water source.

†ppb = parts per billion.

and (3) evidence of indicated transmission from the contaminated source to the potential registrant during the period of exposure as verified by that individual. In the case of the Benzene Subregistry, the well water had to have been tested and validated for the presence of benzene. Also, the well water had to have been the sole source of water for drinking, bathing, or cooking for all individuals at the site residential addresses. Finally, a registrant would had to have reported using the benzene-contaminated well water for drinking, cooking, or bathing for at least 30 days during the exposure period.

Table 2-2.—Contaminants found in the Three Lakes Municipal Utilities District tap and well water, 1990.

Compounds	Maximum Levels (ppb)*
Compounds	Tap	Well
Benzene	66.0	1,100.0
Ethyl benzene	4.1	66.0
Methyl cyclohexane	23.0	30.0
Cyclohexane	7.0	-
Methyl butane	37.0	-
Methyl propane	10.0	70.0
Total trihalomethanes	0.0	31.0
Dibromochloromethane	<1.0	11.0
Bromodichloromethane	<1.0	3.0
Chloroform	<1.0	<1.0
Bromoform	<1.0	17.0
Propane	-	66.0
Dimethyl cyclopentane	-	4.0
Tetramethylcyclopropane	-	42.0
C₃	-	6.0

*ppb - parts per billion

Data collection for the Benzene Subregistry began in 1991 and to date four followups have been completed (Table 2-3). Baseline interviews were conducted face-to-face while followup interviews were conducted via computer-assisted telephone interviews (CATI). Before all interviews, registrants were first sent a mailing that contained information about ATSDR, the NER, the Benzene Subregistry, and the chemical benzene. For the Baseline, a public meeting about the Registry was held in the area prior to the start of data collection.

Table 2-3.—Summary of data collection activities.

Interview Period	Date
Baseline	May 1991-July 1991
Followup 1	June 1992-July 1992
Followup 2	October 1993-September 1994
Followup 3	September 1995-January 1996
Followup 4	September 1997-December 1997

At Baseline, each eligible person or a proxy for that person was administered the NER core questionnaire, which included a set of questions about health conditions that the registrant currently had or had ever had and that had been either confirmed or treated by a health practitioner. Each time the respondent reported the presence of one of these health conditions, a set of follow-up questions was asked about the date of first treatment by a physician, current treatment, prescribed medication, and hospitalization related to the condition.

Information on deceased eligible persons was obtained from a knowledgeable proxy (usually the spouse) and a death certificate was requested from the appropriate state office. Information on cause of death, along with other pertinent information, was extracted from the death certificates and coded as copies of death certificates were obtained from the states. These procedures were the same for the baseline and for all follow-up interviews. Analysis of the mortality data is not included in this report; a separate report on mortality is in progress.

The procedures used for locating registrants for each followup were as follows: four to five weeks before the start of data collection activities, ATSDR began tracing efforts of those registrants known to have moved since the last interview. These tracing cases were usually identified through registrant mailings that were returned to ATSDR as undeliverable. During data collection, cases requiring tracing were identified through attempts made to the telephone number on record. A case was forwarded to a locating specialist if the registrant or proxy had moved (no new telephone number provided), if the telephone number had been disconnected, or if calling the number resulted in "ring no answer" or "busy" (this would be considered a non-working number). The locating specialist would then attempt to locate the registrant by one of the following methods (in the order listed): (1) calling directory assistance; (2) calling contacts provided during the last interview; (3) credit bureau searches; and (4) state departments of motor vehicles searches.

At each followup, and using CATI technology, each registrant or proxy for the registrant was again administered the NER core questionnaire, which includes a set of questions about health practitioner confirmed or treated health conditions that the registrant currently had or had since the last interview. If a respondent reported a health condition, further questions were asked about the date of first treatment, current treatment, prescribed medication, and hospitalization history.

Table 2-4 summarizes the response information from interviews of the exposed registrants at each of the data collection time points and overall. At Baseline, 98% of the eligible people who were contacted and asked to take part in the Benzene Subregistry did participate. Total participation rates were calculated by dividing the number of registrants (living and deceased) who completed interviews by the number of potentially eligible persons who were contacted and asked to participate. By the Followup 4 interviews, 89% of the registrants contacted had agreed to participate. Overall, from Baseline through Followup 4, the Benzene Subregistry has retained about two-thirds (66 %) of the original registrants (including all deceased registrants).

Table 2-4.—Summary of registrant response for the Benzene Subregistry, Baseline through Followup 4, all races.

Outcome	Interview Period
	B*	F†1	F 2	F 3	F 4	Overall
	N (%)§	N (%)	N (%)	N(%)	N(%)	N (%)
Completed interview registrant living	1,127 (96.9)	1,034 (91.7)	950 (91.9)	837 (88.1)	740 (88.4)	740 (63.6)
Completed interview registrant deceased	16 (1.4)	3 (0.3)	4 (0.4)	4 (0.4)	4 (0.5)	31 (2.7)
Refusal	17 (1.5)	23 (2.1)	19 (1.8)	37 (3.9)	46 (5.5)	142 (12.2)
Noninterviewed registrants¶	3 (0.3)	67 (6.0)	61 (5.9)	72 (7.6)	47 (5.6)	250 (21.5)
Total eligible	1,163	1,127	1,034	950	837	1,163

*B = Baseline.

†F = Followup.

§% = percentage of total eligible.

¶Includes unable to locate or contact, unavailable during interview period, language barrier, in litigation, and mentally or physically incapable (with no available proxy).

SECTION 3: METHODS FOR DATA ANALYSES

RATIONALE FOR THE COMPARISON OF THE BENZENE SUBREGISTRY DATA WITH NATIONAL DATA

Benzene Subregistry data were compared with data obtained from the 1989 through 1994 NHIS (6-12) which corresponded to the years in which Benzene Subregistry data were collected. In addition, they most closely correspond to the NER design. In 1995, NHIS radically changed the survey and sampling designs, which precluded comparison of the 1995 NHIS data with NER data. As a result of further changes to the NHIS, subsequent years such as 1996 and 1997 could not be combined with years prior to 1995. The comparison with NHIS data was done to assess differences between the NER and NHIS files in reporting rates for the same or related health effects. These comparisons are consistent with Registry objectives and goals as stated in the Polices and Procedures Manual (1), which are to provide a preliminary assessment of the extent to which Benzene Subregistry members may have an excess, if any, of adverse health conditions and to generate, rather than test, hypotheses about benzene exposure and health outcomes. In addition to a comparison of the subregistry health data with national health data, comparisons of registrant demographic and smoking data with national data were also made to indicate the extent to which Benzene Subregistry members were similar to the general population. These comparisons are important because both demographic characteristics and smoking are known to be correlated with, or are possible causes of, many adverse health conditions.

Subsets of the NHIS data were used in the comparisons with demographic, smoking, and health data components of the Benzene Subregistry. The NHIS is an appropriate comparison population because it is a subset of the residential, noninstitutionalized U.S. population, the population of interest for comparisons of the health status of the NER members. As of 1985, a stratified, multistage cluster sample design was used in the NHIS to obtain a representative sample of the target population; this information was used to create representative national norms. The NHIS, similar to the Registry, consists of self-reported data that were obtained using face-to-face interviews.

Because of the similarity of the data collection instrument and methods used by the NHIS and the NER, the NHIS data were appropriate for the calculation of selected prevalence and incidence statistics and could be used for exploratory comparison with Registry data for health outcomes. The weighting factors (12) provided by the National Center for Health Statistics (NCHS) were applied when using the data. The use of a 6-year composite (1989 through 1994) NHIS rate for the analyses moderated any fluctuations in reporting rates over time. The NHIS files used for selected comparisons in this report contained data from 542,472 respondents.

Members of the Benzene Subregistry reside primarily in the South (Texas), with the remainder located throughout the nation. The influence of regionality on reported disease outcome rates for the Benzene Subregistry, a concern when comparing the subregistry reporting rates with the national rates (reflected by the NHIS numbers) was explored previously (4) and ATSDR's review of the NHIS regional rates for selected outcomes found no definitive evidence indicating that the overall health status of those located in the South differed significantly from that of the general United States population. Therefore, differences between the Benzene Subregistry file and the NHIS file were not expected to be, and did not appear to be, the result of regional differences.

METHODS OF DESCRIPTIVE VARIABLE COMPARISONS

Demographic Characteristics

The NHIS and Benzene Subregistry populations were compared in terms of four demographic characteristics-gender, age, race, and education level-as well as cigarette smoking rates. Each of these variables is a potential correlate of health status.

Gender

The distribution of the male-female ratio was assessed on an age-specific basis. The proportion of males and females in each age category was based on the NHIS data and compared with the corresponding proportions in the Benzene Subregistry. Each age-specific proportion in the Benzene Subregistry was compared with the corresponding proportion in the NHIS by testing that the binomial proportion was equal to a specified theoretical value. No significant differences were found between the two files for this variable at any interview period.

The modeling method used to test differences in reporting rates took into account any effect due to sex. If sex is a significant effect modifier in the Poisson modeling, then comparisons of health rates are made by strata, for males and females. If sex is not significant, the comparison made aggregated over sex is still a sex-adjusted rate. Thus, even if there had been differences in the distributions of males and females in the Benzene Subregistry when compared with the NHIS, the comparisons would not have been affected.

Age

The descriptive comparisons of age used a 10-category measure. The regression analyses in this report involved a regrouping of age categories. An eight-category measure of age (combining the lower two and upper two groups) was used because of the sparsity of positive reports in some of the age strata.

It should be noted that because the health outcome analyses involved summarizing age- and sex-specific comparisons rather than analyzing age-adjusted summaries, whether the age distribution of the NHIS file matched the age distribution of the Benzene Subregistry file was not directly relevant unless distribution differed within the age groups.

The age groupings were realigned in the Followup 1 analysis to compensate for the one-year time lapse since Baseline; that is, 0 through 9 years of age became 1 through 10 years; 10 through 17 years of age became 11 through 18 years, and so forth. The age groupings were similarly adjusted for Followup 2 (1 year difference) and Followups 3 and 4 (2 year differences). The realigned ages were also used for the NHIS age groupings for the statistical analyses.

Race

Race is an established correlate of socioeconomic status (13) and health status (14). National data indicate that nonwhites have lower rates for cigarette smoking (15). For these reasons, race is a potential control variable for the comparisons of health status and smoking rates. However, there were too few nonwhites in the Benzene Subregistry to use race as a variable, so all analyses were restricted to registrants responding white to the race question.

Education Level

For education level (the highest level attained as reported by a respondent), the descriptive analyses at Baseline included comparisons in which education level was measured as a four-category ordinal variable (that is, 0 through 11 years, 12 years or the equivalent of a high school diploma, 13 through 15 years or some college, and 16 years or more or the equivalent of a college degree). The information reflects the status at the time of baseline data collection; therefore, education level was not considered in the analyses of any followup data.

Cigarette Smoking

Rates for current and past smoking behavior were compared across sex, age, and education attainment categories. A current smoker ("current rate") was defined as anyone who reported being a smoker at the time of the interview, and who had smoked at least 100 cigarettes in his or her lifetime. Past smoking behavior ("ever rate") was assessed by calculating the rates for people who had ever smoked at least 100 cigarettes during their lifetime. People who had ever smoked included both current and ex-smokers. For the NHIS, only one adult per household was asked the smoking-related questions; all adults were asked about smoking for the NER.

The comparison of Benzene Subregistry population cigarette smoking rates with a national rate was used as a means to assess the general comparability of the Benzene registrants with the U.S. population, as represented by the NHIS population. Adjustments for smoking or the inclusion of a smoking factor in the regression modeling was not possible because this information was not available for each respondent in the NHIS data. The 1990 through 1994 NHIS did solicit some general smoking information; however, smoking information was not asked of each respondent, but only for one person per household. Therefore, direct comparison of Benzene Subregistry and NHIS smoking rates could not be made, and smoking could not be included in any of the statistical models.

METHODS OF COMPARING HEALTH OUTCOMES

Question Comparability

Prior to comparing Benzene Subregistry and NHIS data for health conditions reported by respondents, the comparability of NHIS and Benzene Subregistry health condition questions was assessed. The questions about health conditions in these two surveys differed in three respects: restrictions on the source of diagnosis; the time frame of occurrence or treatment; and, in some cases, the wording of the health condition. A discussion of each potential source of variation in health condition questions was previously reported (4) and is summarized here. The Benzene Subregistry Baseline health-related questions are in Appendix A; the Benzene Subregistry Followup questions are in Appendix B; and the NHIS health-related questions are in Appendix C.

Source of Diagnosis

Benzene Subregistry questions about health conditions specified that the source of diagnosis must be a "physician or other medical provider". This qualification was intended to minimize self-diagnoses or the biased reporting of health problems by registrants, since they might have a greater awareness of health because of their known exposure and publicity related to the exposure. The NHIS questions did not include any type of qualification concerning the source of diagnosis. Therefore, if all other factors were equal or similar, an increased reporting by NHIS respondents when compared with the registrants might be expected. The increases would be expected to be greater for health conditions often self-diagnosed (for example, arthritis, hearing impairment, and some respiratory problems).

Time Frame

Benzene Subregistry baseline questions about health conditions asked about diagnoses of, or treatment for, conditions from the point of birth through the date of the interview ("Has a physician or other medical provider ever told you/SUBJECT that you/he/she/ had or treated you/SUBJECT for CONDITION?"). Only one time frame was addressed: ever had (subject's lifetime). Respondents who reported "yes" to this question were also asked whether the subject was ever treated for the condition, when the subject was first treated for the condition, and whether the subject was currently being treated for the condition.

Health questions in the Benzene Subregistry follow-up interviews similarly asked about diagnoses of, or treatment for, conditions from the date of the last interview through the date of the current interview. (The time interval between interviews was 1 to 2 years). Respondents who reported "yes" to having been told they had, or were treated for, a condition within the stated time frame were then asked if the date of first treatment was since the last interview, and whether they were currently being treated for the condition.

The NHIS questionnaire included questions that focused on three time frames-ever had the condition, had the condition within the last 12 months, or currently had the condition. With the exception of heart diseases, only one time frame was used to create a response rate for any given health condition. A comparison of NHIS and Benzene Subregistry time frames has been previously described (4). Table 3-1 provides a comparison of NHIS and Benzene Subregistry questions in terms of the time frame for each health condition. One NHIS health condition question, the effects of a stroke, was asked and rate calculated in the context "have you ever had." The questions and time frames for the subregistry and NHIS matched on this condition.

Health Conditions

Benzene Subregistry and NHIS questions were also compared in terms of the phrasing of health conditions. The results of this comparison have been reported previously (4). In summary, some health conditions matched exactly, others did not. Only health questions from the Benzene Subregistry data that were considered to be sufficiently similar to the NHIS health conditions were used for the analyses presented in this report.

Table 3-1.—Comparison of time frames for health condition questions.

(Benzene Subregistry Conversion From "ever had")	National Health Interview Survey Time Frame for Condition
(Benzene Subregistry Conversion From "ever had")	"ever had"	"in the past 12 months"	"now have"
"Ever had" (same)	Stroke
"In the past 12 months" ("Ever had" and "currently have" and/or date of first treatment within past 12 months)		Cancer, rash, anemia, kidney disease, urinary tract disorders, ulcer, liver problems, asthma, respiratory problems and allergies, diabetes, arthritis, hypertension
"Now have" ("Ever had" and "currently have")			Speech impairment, hearing impairment, mental retardation

Calculation of NHIS Rates

Rates of certain health conditions among the general population are calculated, with one difference, as the NCHS directs in their document, Current Health Estimates (16), the companion document to the NHIS data. The difference is, NCHS reports "number of conditions per 1000 people" (a rate), the subregistry calculates "number of people with the condition, per 100 people" (a percentage). Thus, the NCHS rates are not proportions, and can and do count some respondents more than once, if they reported more than one specific condition of the same type. For example, a person may have both stomach ulcer and intestinal ulcers, and each condition reported would be counted in the NCHS method. However, the NER questionnaire used broader categories of conditions and since both conditions are in the same category in our analyses, each person would be counted only once even if they contributed multiple conditions of the same type. Besides collapsing the more numerous and narrowly defined categories of the NHIS data into the broader categories of the NER questionnaire to make comparisons with the subregistry data, the NCHS directions were used to calculate proportions from the NHIS data.

The calculation of the composite or aggregate rate for each category of conditions for the years 1989 through 1994 was also done in the manner directed by NCHS. The person record files and the condition record files are each concatenated across the 6-year period. The total sum, across all six years, of the condition weight times the person weight ("final basic weight") is the numerator of the rate, and the sum across all six years of the person weights is the denominator. (This is done after deleting any condition records that are duplicates for the same person.)

Statistical Analysis of Health Data

The statistical analyses performed treated the NHIS population as a standard population and applied the age- and sex-specific prevalence or period prevalence rates obtained from the NHIS data to the corresponding age- and sex-specific denominators in the Benzene Subregistry. The observed age- and sex-specific numerators for the Benzene Subregistry were compared with the expected numerators based on the NHIS rates.

This one-sample approach ignored sampling variability in the NHIS data because of the large size of the NHIS database relative to the Benzene Subregistry data file. Given that the primary focus of this report is the Benzene Subregistry, treating the NHIS versus Benzene Subregistry comparison as a two-sample problem might have resulted in a dramatic underestimation of the variability associated with the Benzene Subregistry data if any pooled variance estimates were used.

This report used the person-weights (or "final basic weight"[17]) in calculating the health condition rates for NHIS data. To allow for the nonequiprobable sampling in NHIS data, all age- and sex-specific rates that were derived from the NHIS data were weighted by the appropriate person-weights. These weights reflect the complex sampling method used by NCHS in the survey design (17). NCHS does not release with public use data the secondary inclusion (or selection) probabilities that would allow for partial adjustment for the clustering component of the NHIS survey design, so the adjustment was not used in the analyses for this report. The clustering affects only second order (variance and co-variance) estimates, and it is irrelevant because the analyses in this report treat the NHIS data as a population (without sampling error). The age- and sex-specific rates were calculated using only those respondents who were queried about each of the conditions of interest.

Paralleling Poisson regression modeling of standardized mortality ratios, the ratios of the observed-to-expected age- and sex-specific counts were modeled using Poisson regression in the Generalized Linear Interactive Modeling (GLIM) program (18). The Poisson regression approach is described in Breslow and Day (19). Maximum likelihood estimation was used, and likelihood ratio statistics using GLIM. In the Poisson regression analysis, the null model is specified by log(observed) = log(expected) + grand mean. The hypothesis that the rates are the same can be rejected when a confidence interval about the grand mean does not include the value of 1, provided that the null model is adequate. Exact confidence intervals based on the Poisson assumption were used.

By adding terms for age and sex effects to this null model, it was possible to detect structure (confounding) in the ratios of observed-to-expected prevalence rates as a function of these variables.

Statistical Analysis of Cancer Data

For the outcome cancer, incidence data from the 1989 through 1994 NHIS files were used to generate the composite expected numbers, sex- and age- specific, of all cancers. These rates were used for comparison with the observed number in the Benzene Subregistry. The generated expected rates, however, are problematic for Benzene Subregistry comparison purposes. The NHIS rates were asked in the time frame of "in the last 12 months" and are based on the collective information of several specific cancers, not all cancers. Some were queried directly, others ascertained indirectly. The Benzene Subregistry question was asked in the "ever" time frame and for all cancers. To make the Benzene Subregistry database rates comparable to the NHIS rates, the date of first treatment was used as the date of onset and to determine whether onset occurred within "the last 12 months" time frame.

Previously, cancer incidence data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) (20) program were used in addition to NHIS data to generate expected numbers of events for comparison with the Benzene Subregistry observed numbers. This report focuses only on NHIS comparisons. The sparsity of the data for specific cancers in each age category, particularly the younger age groups, precludes statistical comparisons for specific cancers or even for specific age groups. In addition to the follow-up information already collected, ATSDR is making a concerted effort to obtain additional information and carry out further relevant comparisons. A separate report on specific cancers reported by registrants at selected sites is in progress.

SECTION 4: RESULTS OF DESCRIPTIVE COMPARISONS

REGISTRANT DESCRIPTIVE DATA

This section provides a discussion of the comparability of descriptive data for the Benzene Subregistry file and the composite NHIS file. The NHIS and Benzene Subregistry samples were compared in terms of four demographic characteristics-sex, age, race, and education level-as well as cigarette smoking rates. The results of this section were used to plan the subsequent analyses of the health outcome data, that is, to determine what variables were appropriate to include as covariates in modeling the health outcome comparisons.

Tables 4-1 and 4-2 contain information about the characteristics of Benzene Subregistry members at all five time points described in this report; that is, Baseline and Followups 1-4. The subregistry has 1,143 members; 1,127 were living at the time of Baseline data collection and 16 were deceased. Only those living at the time of interview are included in the analyses reported in this document. For the deceased registrants, ATSDR is obtaining death certificates, and will publish a separate report on mortality in the Benzene Subregistry population.

Table 4-1 presents sex, age, education and cigarette smoking data for the composite NHIS population (1989 through 1994) and for the Benzene Subregistry population at all five time points. There were slightly more males than females in the Benzene Subregistry at Baseline through Followup 3; Followup 4 had slightly more females than males. In comparison, the composite NHIS population had slightly more females than males.

The Benzene Subregistry had more people in the youngest age group and fewer people in the three oldest age groups compared to the NHIS composite population. This difference in age

Table 4-1.—Descriptive data for living registrants (whites only), Benzene Subregistry and National Health Interview Survey.

Variable	NHIS*		Baseline		Followup 1		Followup 2		Followup 3		Followup 4
	Percentage of Total by Sex
	M	F	M	F	M	F	M	F	M	F	M	F
Total	48.8	51.2	50.7	49.3	50.5	49.5	50.4	49.6	50.2	49.8	48.4	51.6
Age group^† (years) 0-9 10-17 18-24 25-34 35-44 45-54 55-64 ³65	14.9 11.1 9.6 17.0 16.1 11.3 8.7 11.4	13.5 10.1 9.3 16.3 15.5 11.1 9.1 15.1	25.4 10.4 5.7 27.6 18.7 7.2 2.6 2.4	20.6 11.6 9.1 30.5 15.1 5.7 3.6 3.8	23.2 10.4 5.5 27.4 18.5 7.1 2.4 2.4	20.5 11.6 9.3 31.3 13.9 6.4 3.3 3.5	27.4 10.8 3.5 26.3 20.1 7.1 2.4 2.4	19.6 12.1 9.0 31.9 14.4 6.1 3.6 3.4	29.7 9.8 4.0 26.2 18.6 6.6 2.8 2.3	21.1 10.9 9.6 32.7 12.9 5.8 3.3 3.6	30.7 10.3 4.1 25.1 18.3 5.9 3.5 2.1	21.3 11.6 8.0 33.8 12.5 6.1 3.3 3.3
Education^§ Not high school graduate High school graduate Some college College graduate or more	19.2 35.7 20.5 24.7	19.2 40.2 21.7 19.0	11.9 37.8 29.1 21.2	13.4 43.7 31.7 11.1	10.6 39.1 26.9 23.4	12.2 44.3 31.8 11.6	10.6 36.0 30.0 23.3	9.8 41.4 36.8 12.1	8.1 35.6 31.6 24.7	9.3 43.0 33.7 14.0	7.3 33.0 34.9 24.8	7.2 39.2 38.4 15.2
Cigarette use^¶ Current smoker Ever smoked	27.6 59.8	23.3 44.2	32.0 59.4	27.8 46.9	27.7 55.9	23.6 44.9	27.0 57.8	23.4 42.9	27.7 57.6	24.8 44.6	23.2 54.5	24.1 44.1

*Composite rate from 1989-1994 NHIS data.

†Age at baseline.

§³19 years of age.

¶³18 years of age.

Table 4-2.-Descriptive data for living registrants, Benzene Subregistry only.

Variable	Baseline		Followup 1		Followup 2		Followup 3		Followup 4
	Percentage of Total by Sex
	M	F	M	F	M	F	M	F	M	F
Race White Nonwhite	95.9 4.1	93.1 6.9	95.5 4.5	92.9 7.1	96.2 3.8	92.9 7.1	96.1 3.9	92.9 7.1	96.3 3.7	93.0 7.0
Occupational Status (³19 years of age) Currently employed Previously employed Never employed	91.0 9.0 0.0	66.0 32.0 2.0	NA	NA	NA	NA	NA	NA	NA	NA
Type of Interview Subject Proxy	63.4 36.6	66.0 34.0	62.9 37.1	66.9 33.1	61.8 38.2	68.5 31.5	63.0 37.0	70.5 29.5	65.1 34.9	74.0 26.0

distribution between the two populations remained consistent for all time points. Although the current smoking rates are slightly higher for the Benzene Subregistry population compared with the NHIS population, the ever smoked rates are very similar between the two populations, so smoking was not included as a covariate in the models used for analysis in this report.

Among registrants who were 19 years of age or older, 87% had at least a high school diploma at Baseline. This percentage increased to 93% by Followup 4. At all five time points nearly twice as many males than females had completed college or some post-college education.

Table 4-2 provides data on race, occupational status, and type of interview for all living Benzene Subregistry members only. Benzene registrants were overwhelmingly white (93%-96%); therefore no further analyses were performed on the nonwhite groups because of the small numbers and the potential for violating the confidentiality of the respondents. Analyses of data from all five time points were conducted for this report using only respondents who reported their race as white. Data on occupational status was collected only at Baseline because only changes in employment were captured in follow-up interviews. Most (91%) of the male registrants who were 19 years of age or older at Baseline were currently employed either full- or part-time, compared with 66% of the females.

Decedents were not included in any of the analyses presented in this report. Data collected on deceased registrants was limited to the information required to request death certificates from the state of death, and information obtained from death certificates. No lifestyle information has been or will be solicited for decedents. Death certificates have been obtained for all persons identified as deceased through Followup 4 (n=31). A separate report on mortality in the Benzene Subregistry population is in progress.

Demographic Characteristics

Gender

At Baseline (4) the distribution of the male-female ratio in the NHIS data was compared to the Benzene Subregistry. No statistically significant differences were found between the two files for this variable. Because the sex distribution in the Benzene Subregistry remained relatively constant through all time points, the statistical comparison by sex was not repeated for the followup data.

Race

Because of the small number of nonwhite registrants in the Benzene Subregistry sample (6%), all nonwhite subjects from the NHIS and Benzene Subregistry data were excluded from the analysis reported in this report. The small number and diversity of the nonwhite subpopulation (and also the potential for violating confidentiality) precluded conducting any analyses on this subpopulation.

Age

Previous reports (4) showed that there were not significant differences between the Benzene Subregistry and NHIS populations by age group and by sex within age groups. Because the age distribution in the Benzene Subregistry remained relatively stable for all time points, the age statistical comparison with the NHIS data was not repeated for the followup data.

Education Level

A previous report (4) indicated that the Benzene Subregistry participants had attained a higher level of education than the NHIS population. This difference could modify the comparison of health outcome rates in that the Benzene Subregistry population might be expected to have fewer outcomes related to lower socioeconomic factors. However, because of the small sample size of the Benzene Subregistry, education level is not included as a factor in the regression model.

Cigarette Smoking

A more in-depth review of cigarette use in the Benzene Subregistry compared to the NHIS population was previously reported (4). In summary, the smoking rates by age and sex for the NHIS population and the Benzene Subregistry population were generally very similar at all times, so the omission of smoking as a covariate in any of the statistical models used for this report probably does not impact any of the results.

SECTION 5: RESULTS OF HEALTH OUTCOME COMPARISONS

Overall, aggregate reporting rates for health conditions for the Benzene Subregistry population for each of the time points Baseline through Followup 4 and the NHIS composite population are provided Appendix X, Tables 1 through 5. A summary of the Benzene Subregistry population's reporting rates for specific cancers (total population and by sex) at each of the five data collection time points can be found in Appendix Y, Tables 1-5. A summary of the results of the NHIS and Benzene Subregistry file comparisons using Poisson regression analysis can be found in Appendix Z.

The results for each health condition with statistically significant excess reporting by Benzene Subregistry members are presented, according to the appropriate model, in Table 5-4. A discussion of the statistical results for each health outcome follows. Note, the results for some health outcomes have changed from those reported previously (4) due to the use of composite NHIS comparison values instead of individual year results.

For the results of the statistical analyses presented below, the standardized morbidity ratios (SMR) are presented in Table 5-5 and are defined as the number of each health condition reported by the Benzene Subregistry registrants (observed, O) divided by the number expected based on the number of each health condition reported by the NHIS participants (expected, E). The following discussion is based on the results summaries found in Tables 5-4 and 5-5.

Table 5-4.—Summary of statistically significant results* for health outcomes reported in excess at Baseline.

1. Grand Mean, No Age or Sex Effect.

Structure	Health Condition
Structure	Cancer
Overall Summary	2.44

2. Sex Effect Only.

Sex	Health Condition
Sex	Urinary Tract Disorders
Females	5.60

Table 5-4.—Continued.

3. Age Effect Only.

Age (Years)	Health Condition
Age (Years)	Skin Rash	Kidney Disease	Respiratory Allergies
0-9	2.63		3.43
10-17
18-24
25-34
35-44
45-54
55-64		7.33
³65	4.59

*Significance level: p£0.01
4. By Age and Sex.
(a) Males
No significant excesses for Benzene Subregistry compared with NHIS.
(b) Females.
No significant excess for Benzene Subregistry compared with NHIS.

Table 5-5.–Aggregate observed and expected health outcomes using multivariate models at Baseline.

Condition	Observed	Expected	Risk Ratio	99% CI*
Anemia and other blood disorders^†	40	13.85	2.89	1.85, 4.29
Arthritis^§	46	104.78	0.44	0.29, 0.64
Asthma, emphysema^§	56	101.95	0.55	0.38, 0.77
Cancer^§	13	5.33	2.44	1.05, 4.79
Diabetes^¶	16	14.49	1.10	0.52, 2.03
Hearing impairment^§	13	63.18	0.21	0.09, 0.40
Hypertension^§	60	60.72	0.99	0.69, 1.37
Kidney disease^¶	15	12.13	1.24	0.57, 2.32
Liver problems^§	7	2.17	3.23	0.94, 7.90
Mental retardation^§	2	6.89	0.29	0.02, 1.35
Respiratory allergies^¶	117	108.75	1.08	0.84, 1.36
Skin rashes^¶	89	70.00	1.27	0.95, 1.66
Speech impairment^§	6	11.33	0.53	0.14, 1.38
Stomach problems, ulcers^§	55	62.92	0.87	0.60, 1.23
Stroke^§	10	4.50	2.22	0.83, 4.75
Urinary tract disorders^**	32	8.73	3.67	2.21, 5.69

*CI- Confidence interval for risk ratio.

†No summary model.

§Summary model: grand mean.

¶Summary model: age effect.

**Summary model: sex effect.

§§Summary model: age and sex effect.

Anemia or Other Blood Disorders

There was a statistically significant overall excess of cases reported by members of the Benzene Subregistry population compared to the NHIS population (SMR = 2.84, 99% CI = 1.81-4.21). However, there was no summary model because the model fit was marginal for anemia, thus comparisons to NHIS are best made within age- and sex-specific categories. No significant differences by age and sex were found, due to the small power of these tests.

Arthritis, Rheumatism, or Other Joint Disorders

The overall SMR for this outcome was statistically significant less than 1, indicating that the reporting rates were generally lower in the Benzene Subregistry Baseline data than expected based on NHIS reporting rates (O/E = 0.44, 99% CI = 0.29-0.64).

Asthma, Emphysema, or Chronic Bronchitis

The overall SMR for this outcome was statistically significant less than 1 (O/E = 0.55, 99% CI = 0.38-0.77) indicating a statistically significantly decreased reporting in this group relative to the NHIS population.

Cancers

The overall SMR was statistically significant (O/E = 2.44, 99% CI = 1.05-4.79) meaning there was greater reporting of cancer by the Benzene Subregistry Baseline population compared to the NHIS population. However, the numbers of reported site-specific cancers were too small to perform site-specific statistical analyses. ATSDR is validating reported cancers, and obtaining state and regional cancer rates using state cancer registries for use in further statistical analyses. Results of these analyses, as well as comparison to SEER rates, will provide better insight in interpreting cancer reporting rates. A detailed report on cancer rates in the Benzene Subregistry is forthcoming.

Diabetes

No cases were reported by Benzene Subregistry members at Baseline in the 0 through 9 years, 18 through 24 years, and 45 through 54 years age groups. Ten of the 16 reported cases were reported by those in the 55 through 64 years (O = 6) and 65 years and older (O = 4) age groups. No statistically significant results were seen in any age group.

Hearing Impairment

For this outcome, there was statistically significantly decreased reporting overall for the Benzene Subregistry population compared with the NHIS population (O/E = 0.21, 99% CI = 0.09-0.40).

High Blood Pressure (Hypertension)

No statistically significant results were observed for the Benzene Subregistry reporting rates when compared with the NHIS population reporting rates. The observed number of cases almost exactly matched the expected, resulting in a SMR = 0.99.

Kidney Disease

The model indicated that age was a significant factor. The only statistically significant result was for registrants aged 55 through 64 years (O/E = 7.33, 99% CI = 1.58-20.75).

Liver Problems

There were no reported cases in many of the age- and sex-specific groups. Based on seven reported cases, the overall SMR (3.23) was elevated but was not statistically significant.

Mental Retardation

While the model was adequate, neither sex nor age were significant terms. Only two cases were reported in the Benzene Subregistry Baseline population, yet the results indicated that there was not a statistically significant under-reporting of this condition.

Other Respiratory Allergies or Problems, Such as Hay Fever

The significant factor in the model was age. Statistically significant results were seen in the 0 through 9 years age group (O/E = 3.43, 99% CI = 2.15-5.17).

Skin Rashes, Eczema, or Other Skin Allergies

The significant factor in the model was age. Statistically significant results were observed in the 0 through 9 years of age group (O/E = 2.63, 99% CI = 1.57-4.11) and the 65 years and older age group (O/E = 4.59, 99% CI = 1.97-9.00).

Speech Impairment

Only six cases of speech impairment were reported by Benzene Subregistry members at Baseline. The overall SMR was less than 1 but was not statistically significant.

Effects of Stroke

Although neither the effects of age nor sex were significant in the model, 7 of the 10 cases of stroke reported in the Benzene Subregistry population at Baseline were male. The overall SMR (2.22) was elevated but not statistically significant.

Ulcers, Gallbladder Trouble, and Stomach or Intestinal Problems

Excess reporting in the two youngest age groups resulted in an age effect observed in the model for this outcome. However, no statistically significant results were seen in any age group.

Urinary Tract Disorders, Including Prostate Trouble

Sex was a significant factor in the model, (O/E = 5.60, 99% CI = 3.17-9.10), driven by excess reports of urinary tract disorders by females. Excesses were seen in females in the following age groups: 0 through 9 years, 10 through 17 years, 25 through 34 years, and 35 through 44 years.

SUMMARY

Statistically significant excesses were observed for the following conditions: anemia or other blood disorders; cancer; kidney disease; skin rashes, eczema, or other skin allergies; other respiratory allergies or problems, such as hay fever; and urinary tract disorders, including prostate trouble. Table 5-4 presents a summary of the statistically significant (p£0.01) risk ratios observed in the Poisson analysis of Baseline data for health outcomes reported in excess. Results of health outcome comparisons, aggregated across age and sex, for all health outcomes reported by Benzene Subregistry members at Baseline can be found in Table 5-5.

SECTION 6: RESULTS OF HEALTH OUTCOME COMPARISONS-FOLLOWUP 1

Overall, aggregate reporting rates for health conditions for the Benzene Subregistry file at Followup 1 and the NHIS file are provided in Table 6-1. A summary of the Followup 1 Benzene Subregistry population's reporting rates for specific cancers (total population and by sex) is shown in Table 6-2 for the "within the last 12 months" time frame. The "within last 12 months" time frame is comparable to the NHIS time frame; the 12-month rates were used in the statistical comparisons of the data files. At the time of the interview, if a registrant reported having been told that he or she had cancer or had been treated for cancer by a health care provider, further questions were asked about the type(s) of cancer. Although multiple types of cancers may have been reported, only one primary type of cancer is assigned to each registrant. The summary table entries and data analysis are based on the reported primary cancers.

CONTROLLING FOR AGE AND SEX

Table 6-3 provides a summary of the results of the NHIS and Followup 1 Benzene Subregistry file comparison using Poisson regression analysis. For each health outcome, the table indicates the likelihood ratio statistics with the associated degrees of freedom and p-values for the effects of age (categorized into eight levels) and sex, based on a model containing age and sex. The residual deviance and the associated degrees of freedom are also given as a global lack-of-fit measure for this model, which specifies multiplicative effects of the age (i) and sex (j) ratios Oij/Eij. For each outcome, the age- and sex-specific numerators Oij were obtained from the Benzene Subregistry data, while the

Table 6-1.—Comparison of Benzene Subregistry and National Health Interview Survey participants reporting health condition at Followup 1.

Health Condition	Benzene Subregistry		NHIS
Health Condition	Males †	Females †	Males †	Females †
Anemia and other blood disorders*	1.4	6.4	0.4	2.3
Arthritis*	4.5	5.6	13.2	17.2
Asthma, emphysema*	5.9	8.3	8.7	10.9
Cancer*	1.0	2.3	0.9	1.1
Diabetes*	0.0	0.2	2.3	2.5
Hearing impairment¶	0.8	0.0	10.7	7.1
Hypertension*	6.3	5.8	9.2	10.0
Kidney disease*	0.4	1.7	1.0	1.7
Liver problems*	1.0	0.6	0.3	0.2
Mental retardation¶	0.2	0.0	0.7	0.5
Respiratory allergies*	13.2	17.8	10.3	10.9
Skin rashes*	8.9	10.2	5.8	8.0
Speech impairment¶	0.0	0.0	1.2	0.6
Stomach problems/ulcer*	5.3	7.7	6.4	8.9
Stroke§	1.2	0.8	0.9	1.0
Urinary tract disorders*	4.3	7.5	1.4	1.2

*Indicates time frame is last 12 months.
†Percent of total population (white only).
§Indicates time frame is ever.
¶Indicates time frame is now have.

Table 6-2.—Summary of Benzene Subregistry registrants* reporting at least one cancer at Followup 1.

Cancer	Sex				Total
	Male		Female		Total
	N	%	N	%	N	%
None	487	99.0	471	97.7	958	98.4
Lip, oral, pharynx	0	0.0	0	0.0	0	0.0
Digestive system	0	0.0	0	0.0	0	0.0
Respiratory system	1	0.2	0	0.0	1	0.1
Malignant skin	2	0.4	1	0.2	3	0.3
Breast	0	0.0	4	0.8	4	0.4
Genital organs	1	0.2	5	1.0	6	0.6
Urinary organs	0	0.0	0	0.0	0	0.0
Lymphatic tissues	0	0.0	0	0.0	0	0.0
Leukemia	1	0.2	0	0.0	1	0.1
Other†	0	0.0	1	0.2	1	0.1
Total	492	100.0	482	100.0	974	100.0

*White, exposed registrants only; time frame is "last 12 months."
†Unspecified.

Table 6-3.—Summary of Poisson regression modeling for Followup 1.

Condition	Age/Sex		Sex/Age		Residual Deviance (p-value)	df
Condition	LR Stat* (p-value)	df†	LR Stat (p-value)	df	Residual Deviance (p-value)	df
Anemia and other blood disorders	15.85 (0.03)	7	.051 (0.48)	1	3.86 (0.80)	7
Arthritis	19.90 (0.01)	7	0.00 (0.96)	1	5.63 (0.58)	7
Asthma, emphysema	9.82 (0.20)	7	1.31 (0.25)	1	13.77 (0.06)	7
Cancer	10.11 (0.18)	7	0.66 (0.42)	1	7.23 (0.40)	7
Diabetes	22.68 (0.00)	7	0.61 (0.43)	1	8.67 (0.28)	7
Hearing impairment	9.79 (0.20)	7	3.33 (0.07)	1	0.00 (1.00)	7
Hypertension	5.99 (0.54)	7	0.00 (0.95)	1	4.21 (0.76)	7
Kidney disease	8.34 (0.30)	7	0.77 (0.38)	1	6.79 (0.45)	7
Liver problems	13.50 (0.06)	7	0.13 (0.72)	1	3.80 (0.80)	7
Mental retardation	2.10 (0.95)	7	0.84 (0.36)	1	0.00 (1.00)	7
Respiratory allergies	56.18 (0.00)	7	3.88 (0.05)	1	2.88 (0.90)	7
Skin rashes	25.50 (0.00)	7	0.39 (0.53)	1	9.52 (0.22)	7
Speech impairment	0.00 (1.00)	7	0.00 (1.00)	1	0.00 (1.00)	7
Stomach problems/ulcer	19.53 (0.01)	7	0.01 (0.93)	1	12.49 (0.09)	7
Stroke	16.14 (0.02)	7	0.52 (0.47)	1	3.89 (0.79)	7
Urinary tract disorders	13.67 (0.06)	7	0.65 (0.42)	1	3.41 (0.84)	7

*LR Stat = Likelihood Ratio Statistic.

†df = degrees of freedom.

expected numerators Eij were based on the suitably person-weighted age- and sex-specific ratios from the NHIS data. For the purpose of detecting structure in these age- and sex-specific ratios, a significance level of 0.05 was adopted.

As is shown in Table 6-3, the model was adequate (p>0.1) but neither age nor sex was a statistically significant predictor in the models for the health outcomes cancer; hearing impairment; hypertension; kidney disease; liver problems; mental retardation; speech impairment; and urinary tract disorders, including prostate trouble. For the outcomes anemia and other blood disorders; arthritis, rheumatism or other joint disorders; diabetes; skin rashes, eczema, or other skin allergies; and effects of stroke statistically significant variations in the ratios were seen as a function of age. Sex was not a significant factor in the model for any health outcome. Both age and sex were significant factors in the model for other respiratory allergies or problems, such as hay fever. The model fit was marginal (0.01<p<0.1) for the outcomes asthma, emphysema, or chronic bronchitis; and ulcers, gallbladder trouble, and stomach or intestinal problems.

For the results of the statistical analyses presented below, the standardized morbidity ratios (SMRs) are presented in Table 6-5 and are defined as the number of each health condition reported by the Benzene Subregistry registrants (observed, O) divided by the number expected based on the number of each health condition reported by the NHIS participants (expected, E). The following discussion is based on the results summaries found in Tables 6-4 and 6-5.

Table 6-4.—Summary of statistically significant results* for health outcomes reported in excess at Followup 1.

1. Grand Mean, No Age or Sex Effect.

Structure	Health Condition
Structure	Cancer	Liver Problems	Urinary Tract Disorders
Overall Summary	3.15	3.80	6.89

2. Sex Effect Only.

This model was not applicable for any health condition at Followup 1.

Table 6-4.—Continued.

3. Age Effect Only.

Age (Years)	Health Condition
Age (Years)	Anemia	Arthritis	Skin Rash	Stroke
1-10		7.25	2.93
11-18
19-25
26-35				16.31
36-45
46-55	9.15
56-65	11.68

4. By Age and Sex .

(a) Males.

Age (Years)	Health Condition
Age (Years)	Respiratory Allergies
1-10	3.38

Table 6-4.—Continued.

(b) Females

Age (Years)	Health Condition
Age (Years)	Respiratory Allergies	Stomach Problems, Ulcer
1-10	4.64	4.76
56-65	4.44

*Significance level: p£0.01.

Anemia or Other Blood Disorders

Age was the significant factor in the model for anemia and other blood disorders. Statistically significant results were observed for the age group 46 through 55 years (O/E = 9.15, 99% CI = 2.66-22.38), and the age group 56 through 65 years (O/E = 11.68, 99% CI = 1.96-36.79).

Arthritis, Rheumatism, or Other Joint Disorders

Age had a statistically significant effect in the model due to 4 cases reported in the 1 through 10 years age group (O/E = 7.25, 99% CI = 1.22-22.82). Statistically significant deficits in the Benzene Subregistry Baseline population compared with the NHIS population were seen in the 26 through 35 years and 36 through 45 years of age groups.

Table 6-5.—Summary of observed and expected health outcomes using multivariate models for Followup 1.

Condition	Observed	Expected	Risk Ratio	99% CI*
Anemia and other blood disorders¶	38	12.96	2.93	1.85, 4.39
Arthritis¶	49	99.55	0.49	0.33, 0.70
Asthma, emphysema†	69	95.25	0.72	0.52, 0.98
Cancer§	16	5.08	3.15	1.49, 5.80
Diabetes¶	13	13.74	0.95	0.41, 1.86
Hearing impairment§	4	59.71	0.07	0.01, 0.21
Hypertension§	59	57.50	1.03	0.72, 1.42
Kidney disease§	10	11.31	0.88	0.33, 1.89
Liver problems§	8	2.11	3.80	1.22, 8.83
Mental retardation§	1	6.51	0.15	0.00, 1.14
Respiratory allergies**	151	101.47	1.49	1.20, 1.83
Skin rashes¶	93	65.13	1.43	1.08, 1.86
Speech impairment§	0	10.77	0.00	0.00, 0.43
Stomach problems, ulcers†	63	58.72	1.07	0.76, 1.47
Stroke¶	10	4.24	2.36	0.88, 5.04
Urinary tract disorders§	57	8.27	6.89	4.77, 9.61

*CI - Confidence interval for risk ratio.

†No summary model.

§Summary model: grand mean.

¶Summary model: age effect.

**Summary model: age and sex effect.

Asthma, Emphysema, or Chronic Bronchitis

There was no summary model because the model fit was marginal, thus comparisons to NHIS are best made within age- and sex-specific categories. The only statistically significant result seen for this outcome was a deficit in females aged 11 through 18 years, based on 0 cases reported in the Benzene Subregistry Followup 1 population.

Cancers

The overall SMR (O/E = 3.15) was statistically significant (99% CI = 1.49-5.80) meaning there was greater reporting of cancer by the Benzene Subregistry Followup 1 population compared to the NHIS population. As stated in Section 4, ATSDR is conducting an in-depth analysis of cancers, and will publish the results in a separate report.

Diabetes

Age had a significant effect in the model. Although no statistically significant results were seen in any of the age groups, a slight majority of diabetes cases (7 of 13, or 54%) were reported in the two oldest age groups of the Benzene Subregistry population at Followup 1.

Hearing Impairment

Only four cases of hearing impairment were reported by members of the Benzene Subregistry Followup 1 population. Relative to the NHIS population, there was statistically significantly decreased reporting for the Benzene Subregistry population (O/E = 0.07, 99% CI = 0.01-0.21).

High Blood Pressure (Hypertension)

There were 59 reports of high blood pressure in the Benzene Subregistry Followup 1 population. While the overall SMR was elevated, it was not statistically significant.

Kidney Disease

There were 10 cases of kidney disease reported by the Benzene Subregistry Followup 1 population. No statistically significant results were seen, indicating that reporting of this outcome by Benzene Subregistry members was not very different from that by the NHIS population.

Liver Problems

A statistically significant excess of liver disease was seen in the Benzene Subregistry Followup 1 population compared with the NHIS population (O/E = 3.80, 99% CI = 1.22-8.83). This result is based on 8 cases of liver disease reported by members of the Benzene Subregistry at Followup 1.

Mental Retardation

Only 1 case was reported in the Benzene Subregistry Followup 1 population. The overall SMR was less than 1 but was not statistically significant.

Skin Rashes, Eczema, or Other Skin Allergies

Age was a significant factor in the model. There was an excess reporting of this outcome by the Benzene Subregistry population at Followup1 compared with the NHIS population in the 1 through 10 years of age group (O/E = 2.93, 99% CI = 1.80-4.49).

Speech Impairment

No cases of speech impairment were reported by the Benzene Subregistry population at Followup 1. This result is a statistically significant under-reporting of this condition in the Benzene Subregistry.

Effects of Stroke

The model for effects of stroke indicated that age was a significant factor; statistically significant results were observed in the 26 through 35 years age group (O/E = 16.31, 99% CI = 2.74-51.35).

Ulcers, Gallbladder Trouble, and Stomach or Intestinal Problems

There was no summary model because the model fit was marginal, thus comparisons to NHIS are best made within age- and sex-specific categories. The only statistically significant result was in females aged 1 through 10 years (O/E = 4.76, 99% CI = 1.22-12.41), based on 6 cases. The SMRs were elevated in all age and sex groups up to age 25, and also for males aged 46 through 55 years and females aged 56 through 65 years but none were statistically significant.

Urinary Tract Disorders, Including Prostate Trouble

There was an overall excess of reporting of this outcome in the Benzene Subregistry population at Followup 1 compared with the NHIS population (O/E = 6.89, 99% CI = 4.77-9.61). Although the model was the grand mean, excesses were observed in the following age- and sex-specific groups: males aged 1 through 10 years, females aged 1 through 10 years, females aged 11 through 18 years, females aged 19 through 25 years, males aged 26 through 35 years, females aged 26 through 35 years, males aged 36 through 45 years, and females aged 36 through 45 years.

SUMMARY

Statistically significant excesses were observed for the following conditions: anemia and other blood disorders; arthritis, rheumatism or other joint disorders; cancer; liver problems; skin rashes, eczema, or other skin allergies; other respiratory allergies or problems, such as hay fever; ulcers, gallbladder trouble, and stomach or intestinal problems; effects of stroke; and urinary tract disorders, including prostate trouble. Table 6-4 presents a summary of the statistically significant (p£0.01) risk ratios observed in the Poisson analysis of Followup 1 data for health outcomes reported in excess. Results of health outcome comparisons, aggregated across age and sex, for all health outcomes reported by Benzene Subregistry members at Followup 1 can be found in Table 6-5.

SECTION 7: RESULTS OF HEALTH OUTCOME COMPARISONS-FOLLOWUP 2

Aggregate reporting rates for health conditions for the Benzene Subregistry file at Followup 2 and the NHIS file are provided in Table 7-1. A summary of the Benzene Subregistry Followup 2 population's reporting rates for specific cancers (total population and by sex) is shown in Table 7-2 for the "within the last 12 months" time frame. The "within last 12 months" time frame is comparable to the NHIS time frame; the 12-month rates were used in the statistical comparisons of the data files. At the time of the interview, if registrants reported that a health care provider told them they had cancer or if they had been treated for cancer, further questions were asked about the type(s) of cancer. Although multiple types of cancers may have been reported, only one primary type of cancer is assigned to each registrant. The summary table entries and data analysis are based on the reported primary cancers.

CONTROLLING FOR AGE AND SEX

Table 7-3 summarizes of the results of the NHIS and Benzene Subregistry file comparison using Poisson modeling. For each health outcome, the table indicates the likelihood ratio statistics with the associated degrees of freedom and p-values for the effects of age (categorized into eight levels) and sex, based on a model containing age and sex. The residual deviance and the associated degrees of freedom are also given as a global lack-of-fit measure for this model, which specifies multiplicative effects of the age (i) and sex (j) ratios Oij/Eij. For each outcome, the age- and sex-specific numerators Oij were obtained from the Benzene Subregistry data, while the

Table 7-1.—Comparison of Benzene and National Health Interview Survey participants reporting health condition at Followup 2.

Health condition	Benzene Subregistry		NHIS
Health condition	Males †	Females †	Males †	Females †
Anemia and other blood disorders*	1.3	7.4	0.4	2.3
Arthritis*	4.9	6.7	13.2	17.2
Asthma, emphysema*	6.2	10.3	8.7	10.9
Cancer*	1.3	1.6	0.9	1.1
Diabetes*	1.1	2.5	2.3	2.5
Hearing impairment¶	1.1	1.4	10.7	7.1
Hypertension*	6.8	4.0	9.2	10.0
Kidney disease*	1.1	1.8	1.0	1.7
Liver problems*	1.3	0.2	0.3	0.2
Mental retardation¶	0.0	0.0	0.7	0.5
Respiratory allergies*	18.3	18.7	10.3	10.9
Skin rashes*	5.7	9.7	5.8	8.0
Speech impairment¶	0.7	0.5	1.2	0.6
Stomach problems/ulcer*	6.2	8.8	6.4	8.9
Stroke§	1.1	1.4	0.9	1.0
Urinary tract disorders*	4.0	8.5	1.4	1.2

* Indicates time frame is "last 12 months."

† Indicates percentage of total population (white only).

§ Indicates time frame is "ever."

¶ Indicates time frame is "now have."

Table 7-2.—Summary of Benzene Subregistry registrants reporting at least one cancer at Followup 2.*

Cancer					Total
	Male		Female		Total
	Number	%	Number	%	Number	%
None	447	98.7	438	98.6	885	98.6
Breast	0	0.0	1	0.2	1	0.1
Digestive system	1	0.2	2	0.4	3	0.3
Genital organs	0	0.0	2	0.4	2	0.2
Leukemia	1	0.2	0	0.0	1	0.1
Lip, oral, pharynx	0	0.0	0	0.0	0	0.0
Lymphatic tissues	0	0.0	0	0.0	0	0.0
Malignant skin	4	0.9	2	0.4	6	0.7
Respiratory system	0	0.0	0	0.0	0	0.0
Urinary organs	0	0.0	0	0.0	0	0.0
Other	0	0.0	0	0.0	0	0.0
Total	453	100.0	445	100.0	898	100.0

* White, exposed registrants only; time frame is "last 12 months."

Table 7-3.—Summary of Poisson modeling for Followup 2.

Condition	Age/Sex		Sex/Age		Residual deviance (p-value)	df
Condition	LR stat* (p-value)	df†	LR stat (p-value)	df	Residual deviance (p-value)	df
Anemia and other blood disorders	13.45 (0.06)	7	0.80 (0.37)	1	1.96 (0.96)	7
Arthritis	17.74 (0.01)	7	0.21 (0.64)	1	2.26 (0.94)	7
Asthma, emphysema	5.98 (0.54)	7	3.21 (0.07)	1	6.40 (0.49)	7
Cancer	11.68 (0.11)	7	0.35 (0.55)	1	3.64 (0.82)	7
Diabetes	13.20 (0.07)	7	1.36 (0.24)	1	9.71 (0.20)	7
Hearing impairment	14.12 (0.05)	7	1.00 (0.32)	1	11.58 (0.12)	7
Hypertension	2.74 (0.91)	7	2.83 (0.09)	1	2.80 (0.90)	7
Kidney disease	10.53 (0.16)	7	0.28 (0.60)	1	7.40 (0.39)	7
Liver problems	7.49 (0.38)	7	1.84 (0.17)	1	4.56 (0.71)	7
Mental retardation	0.00 (1.00)	7	0.00 (1.00)	1	0.00 (1.00)	7
Respiratory allergies	40.44 (0.00)	7	0.18 (0.67)	1	170.68 (0.01)	7
Skin rashes	16.80 (0.02)	7	0.47 (0.49)	1	6.90 (0.44)	7
Speech impairment	6.65 (0.47)	7	0.31 (0.58)	1	0.00 (1.00)	7
Stomach problems/ulcer	13.72 (0.06)	7	0.01 (0.92)	1	10.60 (0.16)	7
Stroke	5.21 (0.63)	7	0.00 (0.98)	1	8.52 (0.29)	7
Urinary tract disorders	8.63 (0.28)	7	2.56 (0.11)	1	5.03 (0.66)	7

* LR Stat = Likelihood Ratio Statistic.

† df = degrees of freedom.

As Table 7-3shows, the model was adequate (p > 0.1) but neither age nor sex was a statistically significant predictor in the models for the anemia and other blood disorders; asthma, emphysema, or chronic bronchitis; cancer; diabetes; hypertension; kidney disease; liver problems; mental retardation; speech impairment; ulcers, gallbladder trouble, and stomach or intestinal problems; effects of stroke; and urinary tract disorders, including prostate trouble. Statistically significant variations in the ratios were seen as a function of age arthritis, rheumatism or other joint disorders; hearing impairment; and skin rashes, eczema, or other skin allergies. Sex was not a significant factor in the model for any health outcome. The model fit was marginal (0.01 < p < 0.1) for other respiratory allergies or problems, such as hay fever.

The results for each health condition with statistically significant excess reporting by Benzene subregistry registrants are presented, according to the appropriate model, in Table 7-4. A discussion of the statistical results for each health outcome follows.

For the results of the statistical analyses presented below, the SMRs are in Table 7-5 and are defined as the number of each health condition reported by the Benzene Subregistry registrants (observed, O) divided by the number expected based on the number of each health condition reported by the NHIS participants (expected, E). The following discussion is based on the results summaries in Tables 7-4 and 7-5.

Table 7-4.—Summary of statistically significant results for health outcomes reported in excess for Followup 2.*

1. Grand mean, no age or sex effect.

Structure	Health condition
Structure	Anemia	Cancer	Liver problems	Effects of stroke	Urinary tract disorders
Overall summary	3.30	2.61	3.45	2.66	7.07

2. Sex effect only.

This model was not applicable for any health condition at Followup 2.

3. Age Effect Only.

No significant excesses for Benzene Subregistry compared with NHIS.

Table 7-4.—Continued.

4. By age and sex.

(a) Males.

Age(years)	Health condition
Age(years)	Respiratory allergies
2-11	3.20

(b) Females.

Age(years)	Health conditions
Age(years)	Respiratory allergies
2-11	5.17

* Significance level: p £ 0.01.

Anemia or Other Blood Disorders

The overall SMR (O/E = 3.30) was statistically significant (99% CI = 2.10-4.93). Excesses were also observed for females aged 20 - 26, 27 - 36, and 57 - 66.

Table 7-5.—Summary of observed and expected health outcomes using multivariate models for Followup 2.

Condition	Observed	Expected	Risk ratio	99% CI*
Anemia and other blood disorders§	39	11.81	3.30	2.10, 4.93
Arthritis¶	52	96.70	0.54	0.37, 0.76
Asthma, emphysema§	74	88.73	0.83	0.61, 1.12
Cancer§	13	4.98	2.61	1.12, 5.12
Diabetes§	16	13.46	1.19	0.56, 2.19
Hearing impairment¶	11	57.58	0.19	0.08, 0.40
Hypertension§	49	56.47	0.87	0.58, 1.24
Kidney disease§	13	10.75	1.21	0.52, 2.37
Liver problems§	7	2.03	3.45	1.00, 8.44
Mental retardation§	0	6.24	0.00	0.00, 0.74
Respiratory allergies†	166	95.45	1.74	1.41, 2.12
Skin rashes¶	69	60.98	1.13	0.81, 1.53
Speech impairment§	5	10.22	0.49	0.11, 1.39
Stomach problems, ulcers§	67	55.77	1.20	0.86, 1.63
Stroke§	11	4.13	2.66	1.05, 5.52
Urinary tract disorders§	56	7.92	7.07	4.87, 9.89

* CI - Confidence interval for risk ratio.
† No summary model.
§ Summary model: grand mean.
¶Summary model: age effect.

Arthritis, Rheumatism, or Other Joint Disorders

For this outcome, there was statistically significantly decreased reporting by Benzene Subregistry population compared with the NHIS population (O/E = 0.54, 99% CI = 0.37-0.76). There were four cases in the youngest age group, resulting in an elevated SMR for Benzene registrants in this age group relative to the NHIS population, however, this ratio was not statistically significant (O/E = 5.95, 99% CI = 1.00-18.72).

Asthma, Emphysema, or Chronic Bronchitis

No statistically significant results were seen, indicating that reporting of this outcome by Benzene Subregistry registrants was not very different from that by the NHIS population.

Cancers

The overall SMR (O/E = 2.61) was statistically significant (99% CI = 1.12-5.12) meaning there was greater reporting of cancer by the Benzene Subregistry Followup 2 population compared to the NHIS population. ATSDR is conducting an in-depth analysis of cancers, and will publish the results in a separate report.

Diabetes

No statistically significant results seen, although excess cases were reported in the two youngest age groups. Although SMRs were elevated for several age groups, none were statistically significant.

Hearing Impairment

Statistically significant deficits were observed in several age groups and the overall SMR was statistically significantly less than 1 indicating less reporting of this condition by Benzene Subregistry Followup 2 registrants compared with the NHIS population.

Hypertension

No statistically significant results were seen, indicating that reporting of this outcome by Benzene Subregistry registrants was not very different from that by the NHIS population.

Kidney Disease

No statistically significant results were seen, indicating that reporting of this outcome by Benzene Subregistry registrants was not very different from that by the NHIS population.

Liver Problems

A statistically significant excess of liver disease was seen by Benzene Subregistry Followup 2 population compared with the NHIS population (O/E = 3.45, 99% CI = 1.00-4.93). This result is based on seven cases of liver disease reported by Benzene Subregistry registrants at Followup 2.

Mental Retardation

No cases of mental retardation were reported by the Benzene Subregistry population at Followup 2; 6.2 cases were expected based on results from the NHIS population.

Other Respiratory Allergies or Problems, Such as Hay Fever

There was no summary model because the model fit was marginal, thus comparisons to NHIS are best made within age- and sex-specific categories. Statistically significant results were seen for males aged 2 - 11 (O/E = 3.21, 99% CI = 1.79-5.26), and females 2 -11 (O/E = 5.17, 99% CI = 2.93-8.40).

Skin Rashes, Eczema, or Other Skin Allergies

Age was a factor in the model due to a statistically nonsignificant excess of reports in the youngest age group of the Benzene Subregistry Followup 2. No statistically significant results were seen in any age group.

Speech Impairment

No statistically significant results were seen, indicating that reporting of this outcome by Benzene Subregistry registrants was not very different from that by the NHIS population.

Effects of Stroke

The overall SMR was statistically significantly elevated for Benzene Subregistry population at Followup 2 compared with the NHIS population reporting rates (O/E = 2.66, 99% CI = 1.05-5.52). The ratio for females aged 27 - 36 was also elevated but was based on only two cases.

Ulcers, Gallbladder Trouble, and Stomach or Intestinal Problems

No statistically significant results were seen, indicating that reporting of this outcome by Benzene Subregistry registrants was not very different from that by the NHIS population.

Urinary Tract Disorders, Including Prostate Trouble

There was an overall excess of reporting of urinary tract disorders in the Benzene Subregistry population at Followup 2 compared with the NHIS population (O/E = 7.07, 99% CI = 4.87-9.89). Excesses were seen for females aged 2 -11, 20 - 26, 27 - 36, and males and females aged 37 - 46.

SUMMARY

Statistically significant excesses were observed anemia and other blood disorders; cancer; liver problems; other respiratory allergies or problems, such as hay fever; effects of stroke; and urinary tract disorders, including prostate trouble. Table 7-4 summarizes of the statistically significant (p £ 0.01) risk ratios observed in the Poisson modeling of Followup 2 data for health outcomes reported in excess. Results of health outcome comparisons, aggregated across age and sex, for all health outcomes reported by Benzene Subregistry registrants at Followup 2 are in Table 7-5.

SECTION 8: RESULTS OF HEALTH OUTCOME COMPARISONS-FOLLOWUP 3

Aggregate reporting rates for health conditions for the Benzene Subregistry file at Followup 3 and the NHIS file are provided in Table 8-1. A summary of the Benzene Subregistry Followup 3 population's reporting rates for specific cancers (total population and by sex) is shown in Table 8-2 for the "within the last 12 months" time frame. The "within last 12 months" time frame is comparable to the NHIS time frame; the 12-month rates were used in the statistical comparisons of the data files. At the time of the interview, if a registrant reported that a health care provider told them they had cancer or if they had been treated for cancer, further questions were asked about the type(s) of cancer. Although multiple types of cancers may have been reported, only one primary type of cancer is assigned to each registrant. The summary table entries and data analysis are based on the reported primary cancers.

CONTROLLING FOR AGE AND SEX

Table 8-3 summarizes of the results of the NHIS and Benzene Subregistry Followup 3 file comparison using Poisson modeling analysis. For each health outcome, the table indicates the likelihood ratio statistics with the associated degrees of freedom and p-values for the effects of age (categorized into eight levels) and sex, based on a model containing age and sex. The residual deviance and the associated degrees of freedom are also given as a global lack-of-fit measure for this model, which specifies multiplicative effects of the age (i) and sex (j) ratios Oij/Eij. For each outcome,

Table 8-1.-Comparison of Benzene and National Health Interview Survey participants reporting health condition at Followup 3.

Health condition	Benzene Subregistry		NHIS
Health condition	Males †	Females †	Males †	Females †
Anemia and other blood disorders*	1.3	6.6	0.4	2.3
Arthritis*	8.1	7.6	13.2	17.2
Asthma, emphysema*	8.1	11.9	8.7	10.9
Cancer*	2.0	1.0	0.9	1.1
Diabetes*	2.3	2.0	2.3	2.5
Hearing impairment¶	0.5	0.3	10.7	7.1
Hypertension*	9.1	6.4	9.2	10.0
Kidney disease*	1.8	1.0	1.0	1.7
Liver problems*	0.3	0.8	0.3	0.2
Mental retardation¶	0.3	0.0	0.7	0.5
Respiratory allergies*	19.9	20.1	10.3	10.9
Skin rashes*	9.1	11.2	5.8	8.0
Speech impairment¶	1.0	0.3	1.2	0.6
Stomach problems/Ulcer*	7.3	7.9	6.4	8.9
Stroke§	1.8	1.8	0.9	1.0
Urinary tract disorders*	4.0	11.4	1.4	1.2

* Indicates time frame is "last 12 months."
† Indicates Percentage of total population (white only).
§ Indicates time frame is "ever".
¶ Indicates time frame is "now have".

Table 8-2.—Summary of Benzene Subregistry registrants reporting at least one cancer at Followup 3.*

Cancer					Total
	Male		Female		Total
	N	%	N	%	N	%
None	389	97.9	390	98.9	779	98.4
Breast	0	0.0	0	0.0	0	0.0
Digestive system	0	0.0	0	0.0	0	0.0
Genital organs	2	0.5	1	0.3	3	0.4
Leukemia	1	0.3	0	0.0	1	0.1
Lip, oral, pharynx	0	0.0	0	0.0	0	0.0
Lymphatic tissues	0	0.0	1	0.3	1	0.1
Malignant skin	3	0.8	2	0.5	5	0.7
Respiratory system	0	0.0	0	0.0	0	0.0
Urinary organs	0	0.0	0	0.0	0	0.0
Other†	2	0.5	0	0.0	2	0.3
Total	397	100.0	394	100.0	791	100.0

* White, exposed registrants only; time frame is "last 12 months."

† Includes: bone, Kaposi's sarcoma.

Table 8-3.—Summary of Poisson modeling for Followup 3.

Condition	Age/Sex		Sex/Age		Residual Deviance (p-value)	df
Condition	LR Stat* (p-value)	df†	LR Stat (p-value)	df	Residual Deviance (p-value)	df
Anemia and other blood disorders	7.34 (0.39)	7	0.77 (0.38)	1	5.41 (0.61)	7
Arthritis	12.97 (0.07)	7	0.77 (0.38)	1	1.92 (0.96)	7
Asthma, emphysema	4.38 (0.73)	7	1.44 (0.23)	1	10.43 (0.16)	7
Cancer	3.87 (0.79)	7	2.50 (0.11)	1	3.63 (0.82)	7
Diabetes	19.72 (0.01)	7	0.21 (0.65)	1	7.30 (0.40)	7
Hearing impairment	5.93 (0.55)	7	0.26 (0.61)	1	1.30 (0.99)	7
Hypertension	8.93 (0.26)	7	2.19 (0.14)	1	9.83 (0.20)	7
Kidney disease	8.11 (0.32)	7	2.09 (0.15)	1	9.47 (0.22)	7
Liver problems	7.84 (0.35)	7	2.17 (0.14)	1	2.15 (0.95)	7
Mental retardation	1.19 (0.99)	7	0.74 (0.39)	1	0.00 (1.00)	7
Respiratory allergies	22.15 (0.00)	7	0.05 (0.82)	1	3.40 (0.85)	7
Skin rashes	3.54 (0.83)	7	0.22 (0.64)	1	6.80 (0.45)	7
Speech impairment	7.48 (0.38)	7	0.30 (0.58)	1	0.72 (1.00)	7
Stomach problems/ulcer	16.68 (0.02)	7	1.08 (0.30)	1	11.95 (0.10)	7
Stroke	11.18 (0.13)	7	0.00 (0.99)	1	10.12 (0.18)	7
Urinary tract disorders	10.53 (0.16)	7	7.17 (0.01)	1	6.23 (0.51)	7

*LR Stat = Likelihood Ratio Statistic.
† df = degrees of freedom.

the age- and sex-specific numerators Oij were obtained from the Benzene Subregistry data, while the expected numerators Eij were based on the suitably person-weighted age- and sex-specific ratios from the NHIS data. For the purpose of detecting structure in these age- and sex-specific ratios, a significance level of 0.05 was adopted.

As Table 8-3 shows, the model was adequate (p > 0.1) but neither age nor sex was a statistically significant predictor in the models for anemia and other blood disorders; arthritis, rheumatism or other joint disorders; asthma, emphysema, or chronic bronchitis; cancer; hearing impairment; hypertension; kidney disease; liver problems; mental retardation; skin rashes, eczema, or other skin allergies; speech impairment; and effects of stroke. For urinary tract disorders, including prostate trouble, the effects of sex were statistically significant. Statistically significant variations in the ratios were seen as a function of age for diabetes; other respiratory allergies or problems, such as hay fever; and ulcers, gallbladder trouble, and stomach or intestinal problems.

The results for each health condition with statistically significant excess reporting by Benzene Subregistry registrants are presented, according to the appropriate model, in Table 8-4. A discussion of the statistical results for each health outcome follows.

For the results of the statistical analyses presented below, the SMRs are in Table 8-5 and are defined as the number of each health condition reported by the Benzene Subregistry registrants (observed, O) divided by the number expected based on the number of each health condition reported by the NHIS participants (expected, E). The following discussion is based on the results summaries in Tables 8-4 and 8-5.

Table 8-4.—Summary of statistically significant results for health outcomes reported in excess for Followup 3.*

1. Grand mean, no age or sex effect.

Structure	Health condition
Structure	Anemia	Cancer	Skin Rash	Effects of Stroke
Overall summary	2.99	2.49	1.48	3.38

2. Sex effect only.

Sex	Health condition
Sex	Urinary tract disorders
Males	4.28
Females	11.85

Table 8-4.—Continued 3. Age effect only.

Age (years)	Health condition
Age (years)	Diabetes	Respiratory allergies	Stomach problems, ulcer
4-13		3.26	4.64
14-21
22-28
29-38
39-48		1.82
49-58
59-68	3.47
³69

*Significance level: p £ 0.01.

4. By age and sex .

(a) Males and females.

No significant excesses for Benzene Subregistry compared with NHIS.

Anemia or Other Blood Disorders

There was an overall excess of reporting of anemia or other blood disorders in the Benzene Subregistry population at Followup 3 compared with the NHIS population (O/E = 2.99, 99% CI = 1.79-4.67). There was also excess reporting by females aged 29 - 38.

Arthritis, Rheumatism, or Other Joint Disorders

There was statistically significantly decreased reporting for Benzene Subregistry population compared with the NHIS population (O/E = 0.68, 99% CI = 0.48-0.93).

Table 8-5.—Summary of observed and expected health outcomes using multivariate models for Followup 3.

Condition	Observed	Expected	Risk ratio	99% CI*
Anemia and other blood disorders§	31	10.37	2.99	1.79, 4.67
Arthritis§	62	91.40	0.68	0.48, 0.93
Asthma, emphysema§	79	78.78	1.00	0.74, 1.33
Cancer§	12	4.82	2.49	1.03, 5.01
Diabetes¶	17	12.81	1.33	0.64, 2.40
Hearing impairment§	3	54.36	0.06	0.01, 0.20
Hypertension§	61	53.84	1.13	0.79, 1.56
Kidney disease§	11	9.73	1.13	0.44, 2.34
Liver problems§	4	1.91	2.10	0.35, 6.60
Mental retardation§	1	5.88	0.17	0.00, 1.26
Respiratory allergies¶	160	86.13	1.86	1.50, 2.27
Skin rashes§	80	54.05	1.48	1.09, 1.96
Speech impairment§	5	9.28	0.54	0.12, 1.53
Stomach problems, ulcers¶	60	51.23	1.17	0.82, 1.62
Stroke§	14	4.14	3.38	1.51, 6.49
Urinary tract disorders**	61	7.53	8.10	5.68, 11.17

* CI - Confidence interval for risk ratio.
† No summary model.
§ Summary model: grand mean.
¶ Summary model: age effect.
** Summary model: sex effect.

Asthma, Emphysema, or Chronic Bronchitis

No statistically significant results were seen, indicating that reporting of this outcome by Benzene Subregistry registrants was not very different from that by the NHIS population.

Cancers

The overall SMR (O/E = 2.49) was statistically significant (99% CI = 1.03-5.01) meaning there was greater reporting of cancer by the Benzene Subregistry Followup 3 population compared to the NHIS population. ATSDR is conducting an in-depth analysis of cancers, and will publish the results in a separate report.

Diabetes

Age was a factor in the model, and there was a statistically significant increase in the age group 59 - 68 (O/E = 3.47, 99% CI = 1.01-8.49).

Hearing Impairment

There was statistically significantly decreased reporting for Benzene Subregistry registrants compared with the NHIS population (O/E = 0.06, 99% CI = 0.01-0.20). Only three cases were reported by Benzene Subregistry registrants.

Hypertension

No statistically significant results were seen, indicating that reporting of this outcome by Benzene Subregistry registrants was not very different from that by the NHIS population.

Kidney Disease

No statistically significant results were seen, indicating that reporting of this outcome by Benzene Subregistry registrants was not very different from that by the NHIS population.

Liver Problems

Only four cases of liver disease were reported by Benzene Subregistry registrants at Followup 3. Although the overall SMR was elevated, it was not statistically significant.

Mental Retardation

Only one case of mental retardation was reported by Benzene Subregistry registrants at Followup 3. No statistically significant results were seen.

Skin Rashes, Eczema, or Other Skin Allergies

The overall SMR (O/E = 1.48) was statistically significant (99% CI = 1.09-1.96) meaning there was greater reporting of this condition by Benzene Subregistry Followup 3 population compared to the NHIS population.

Speech Impairment

Only five cases of speech impairment were reported by Benzene Subregistry registrants at Followup 3. No statistically significant results were seen.

Effects of Stroke

The overall SMR (O/E = 3.38) was statistically significant (99% CI = 1.51-6.49) meaning there was greater reporting of this condition by the Benzene Subregistry Followup 3 population compared to the NHIS population.

Ulcers, Gallbladder Trouble, and Stomach or Intestinal Problems

Age was indicated as a factor in the model, and a statistically significant result was seen in the age group 3 - 12 (O/E = 4.65, 99% CI = 1.73, 9.94) based on 10 reported cases.

Urinary Tract Disorders, Including Prostate Trouble

There was an overall sex effect for urinary tract disorders. The statistically significant excess of reporting was larger for females (O/E = 11.85, 99% CI = 7.80-17.21) than for males (O/E = 4.28, 99% CI = 2.02-7.89).

SUMMARY

Statistically significant excesses were observed for anemia and other blood disorders; cancer; diabetes; other respiratory allergies or problems, such as hay fever; skin rashes, eczema, or other skin allergies; effects of stroke; ulcers, gallbladder trouble, and stomach or intestinal problems; and urinary tract disorders, including prostate trouble. Table 8-4 summarizes the statistically significant (p £ 0.01) risk ratios observed in the Poisson analysis of Followup 3 data for health outcomes reported in excess. Results of health outcome comparisons, aggregated across age and sex, for all health outcomes reported by Benzene Subregistry registrants at Followup 3 are in Table 8-5.

SECTION 9: RESULTS OF HEALTH OUTCOME COMPARISONS-FOLLOWUP 4

Aggregate reporting rates for health conditions for the Benzene Subregistry file at Followup 4 and the NHIS file are provided in Table 9-1. A summary of the Benzene Subregistry Followup 4 population's reporting rates for specific cancers (total population and by sex) is shown in Table 9-2 for the "within the last 12 months" time frame. The "within last 12 months" time frame is comparable to the NHIS time frame; the 12-month rates were used in the statistical comparisons of the data files. At the time of the interview, if a registrant reported that a health care provider told them they had cancer or if they had been treated for cancer, further questions were asked about the type(s) of cancer. Although multiple types of cancers may have been reported, only one primary type of cancer is assigned to each registrant. The summary table entries and data analysis are based on the reported primary cancers.

CONTROLLING FOR AGE AND SEX

Table 9-3 summarizes the results of the NHIS and Benzene Subregistry Followup 4 file comparison using Poisson modeling. For each health outcome, the table indicates the likelihood ratio statistics with the associated degrees of freedom and p-values for the effects of age (categorized into eight levels) and sex, based on a model containing age and sex. The residual deviance and the associated degrees of freedom are also given as a global lack-of-fit measure for this model, which specifies multiplicative effects of the age (i) and sex (j) ratios Oij/Eij. For each outcome, the age- and sex-specific numerators Oij were obtained from the Benzene Subregistry data, while the

Table 9-1.—Comparison of Benzene and National Health Interview Survey participants reporting health condition at Followup 4.

Health Condition	Benzene Subregistry		NHIS
Health Condition	Males †	Females †	Males†	Females†
Anemia and other blood disorders*	3.0	7.8	0.4	2.3
Arthritis*	8.0	12.5	13.2	17.2
Asthma, emphysema*	7.1	10.5	8.7	10.9
Cancer*	2.1	1.1	0.9	1.1
Diabetes*	3.2	1.7	2.3	2.5
Hearing impairment¶	0.9	1.1	10.7	7.1
Hypertension*	11.5	6.7	9.2	10.0
Kidney disease*	1.2	1.1	1.0	1.7
Liver problems*	0.6	1.1	0.3	0.2
Mental retardation¶	0.6	0.0	0.7	0.5
Respiratory allergies*	21.8	23.8	10.3	10.9
Skin rashes*	8.9	11.9	5.8	8.0
Speech impairment¶	0.3	0.0	1.2	0.6
Stomach problems/ulcer*	7.1	9.1	6.4	8.9
Stroke§	2.1	2.2	0.9	1.0
Urinary tract disorders*	2.7	9.1	1.4	1.2

* Indicates time frame is "last 12 months."
† Indicates percentage of total population (white only).
§ Indicates time frame is "ever."
¶ Indicates time frame is "now have."

Table 9-2.—Summary of Benzene Subregistry registrants reporting at least one cancer at Followup 4.*

Cancer					Total
	Male		Female		Total
	Number	%	Number	%	Number	%
None	332	97.9	357	98.8	689	98.5
Breast	0	0.0	1	0.3	1	0.1
Digestive system	1	0.3	1	0.3	2	0.4
Genital organs	2	0.6	1	0.3	3	0.4
Leukemia	1	0.3	0	0.0	1	0.1
Lip, oral, pharynx	0	0.0	0	0.0	0	0.0
Lymphatic tissues	0	0.0	0	0.0	0	0.0
Malignant skin	3	0.9	1	0.3	4	0.5
Respiratory system	0	0.0	0	0.0	0	0.0
Urinary organs	0	0.0	0	0.0	0	0.0
Other	0	0.0	0	0.0	0	0.0
Total	339	100.0	361	100.0	700	100.0

* White, exposed registrants only; time frame is "last 12 months."

Table 9-3.—Summary of Poisson modeling for Followup 4.

Condition	Age/Sex		Sex/Age		Residual deviance (p-value)	df
Condition	LR Stat* (p-value)	df†	LR Stat (p-value)	df	Residual deviance (p-value)	df
Anemia and other blood disorders	6.62 (0.47)	7	4.18 (0.04)	1	3.30 (0.86)	7
Arthritis	6.90 (0.44)	7	0.75 (0.39)	1	6.51 (0.48)	7
Asthma, emphysema	12.51 (0.09)	7	1.08 (0.30)	1	13.11 (0.07)	7
Cancer	4.60 (0.71)	7	1.79 (0.18)	1	8.03 (0.33)	7
Diabetes	12.87 (0.08)	7	1.49 (0.22)	1	8.88 (0.26)	7
Hearing impairment	10.84 (0.15)	7	0.90 (0.34)	1	2.30 (0.94)	7
Hypertension	12.23 (0.09)	7	4.62 (0.03)	1	5.97 (0.54)	7
Kidney disease	6.17 (0.52)	7	0.27 (0.61)	1	6.11 (0.53)	7
Liver problems	4.51 (0.72)	7	1.35 (0.24)	1	6.64 (0.47)	7
Mental retardation	2.16 (0.95)	7	1.86 (0.17)	1	0.00 (1.00)	7
Respiratory allergies	14.02 (0.05)	7	0.04 (0.84)	1	5.08 (0.65)	7
Skin rashes	12.74 (0.08)	7	0.00 (0.97)	1	6.97 (0.43)	7
Speech impairment	1.16 (0.99)	7	0.65 (0.42)	1	0.00 (1.00)	7
Stomach problems/ulcer	9.73 (0.20)	7	0.05 (0.81)	1	9.40 (0.22)	7
Stroke	8.03 (0.33)	7	0.04 (0.83)	1	6.88 (0.44)	7
Urinary tract disorders	2.77 (0.90)	7	9.83 (0.00)	1	11.80 (0.11)	7

* LR Stat = Likelihood Ratio Statistic.

† df = degrees of freedom.

As Table 9-3 shows, the model was adequate (p > 0.1) but neither age nor sex was a statistically significant predictor in the models for arthritis, rheumatism or other joint disorders; cancer; diabetes; hearing impairment; kidney disease; liver problems; mental retardation; other respiratory allergies or problems, such as hay fever; skin rashes, eczema, or other skin allergies; speech impairment; ulcers, gallbladder trouble, and stomach or intestinal problems; and effects of stroke. Age was not a significant factor in the model for any health outcome. For anemia and other blood disorders; hypertension; and urinary tract disorders, including prostate trouble, the effects of sex were statistically significant. The model fit was marginal (0.01 < p < 0.1) for asthma, emphysema, or chronic bronchitis.

The results for each health condition with statistically significant excess reporting by Benzene Subregistry registrants are presented, according to the appropriate model, in Table 9-4. A discussion of the statistical results for each health outcome follows.

For the results of the statistical analyses presented below, the SMRs are in Table 9-5 and are defined as the number of each health condition reported by the Benzene Subregistry registrants (observed, O) divided by the number expected based on the number of each health condition reported by the NHIS participants (expected, E). The following discussion is based on the results summaries in Tables 9-4 and 9-5.

Table 9-4.—Summary of statistically significant results for health outcomes reported in excess for Followup 4.*

1. Grand mean, no age or sex effect.

Structure	Health Condition
Structure	Skin rash	Respiratory allergies	Effects of stroke
Overall summary	1.49	2.05	3.59

2. Sex effect only.

Sex	Health condition
Sex	Anemia	Urinary tract disorders
Males	8.54
Females	3.46	9.12

*Significance level: p £ 0.01.
3. Age effect only.

This model was not applicable for any health condition at Followup 4.

Table 9-4.—Continued.

4. By age and sex.Males and females.

This model was not applicable for any health condition at Followup 4.

Anemia or Other Blood DisordersThere was a sex effect in the reporting of anemia or other blood disorders in Benzene Subregistry population at Followup 4 compared with the NHIS population. This effect was more pronounced for males (O/E = 8.54, 99% CI = 3.18-18.28) than for females (O/E = 3.46, 99% CI = 2.01-5.52) although males accounted for only about one-third of the reported cases (10/28).

Table 9-5.—Summary of observed and expected health outcomes using multivariate models for Followup 4.

Condition	Observed	Expected	Risk Ratio	99% CI*
Anemia and other blood disorders**	38	9.28	4.10	2.59, 6.14
Arthritis§	72	88.86	0.81	0.59, 1.09
Asthma, emphysema†	62	70.03	0.89	0.62, 1.22
Cancer§	11	4.82	2.28	0.90, 4.73
Diabetes§	17	12.56	1.35	0.66, 2.45
Hearing impairment§	7	51.55	0.14	0.04, 0.33
Hypertension**	63	52.46	1.20	0.85, 1.65
Kidney disease§	8	8.93	0.90	0.29, 2.08
Liver problems§	6	1.74	3.45	0.89, 9.02
Mental retardation§	2	5.52	0.36	0.02, 1.68
Respiratory allergies§	160	78.19	2.05	1.65, 2.50
Skin rashes§	73	48.88	1.49	1.08, 2.01
Speech impairment§	1	7.49	0.13	0.00, 0.99
Stomach problems, ulcers§	57	47.86	1.19	0.82, 1.66
Stroke§	15	4.18	3.59	1.65, 6.74
Urinary tract disorders**	42	7.20	5.84	3.78, 8.58

* CI - Confidence interval for risk ratio.
† No summary model.
§ Summary model: grand mean.
¶ Summary model: age effect.
** Summary model: sex effect.

Arthritis, Rheumatism, or Other Joint Disorders

The 99% CI for the overall SMR includes 1; no statistically significant results were seen.

Asthma, Emphysema, or Chronic Bronchitis

There was no summary model because the model fit was marginal, thus comparisons to NHIS are best made within age- and sex-specific categories. No significant differences by age and sex were found.

Cancers

The overall SMR was elevated but was not statistically significant. ATSDR is conducting an in-depth analysis of cancers, and will publish the results in a separate report.

Diabetes

The overall SMR was elevated but was not statistically significant.

Hearing Impairment

With only seven cases, the overall SMR for the Benzene Subregistry was statistically significantly lower than for NHIS. Deficits were seen for males in the age group 31 - 40 and 41 - 50 , and for females in the age group 31- 40.

Hypertension

The overall SMR was elevated but not statistically significant. No statistically significant results were seen for either sex.

Kidney Disease

Only eight cases of kidney disease were reported by Benzene Subregistry registrants at Followup 4. No statistically significant results were seen.

Liver Problems

The overall SMR was elevated but not statistically significant. Only six cases of liver problems were reported by Benzene Subregistry registrants at Followup 4.

Mental Retardation

Based on only two cases of mental retardation reported by Benzene Subregistry registrants at Followup 4, the overall SMR was lower compared to the NHIS results but was not statistically significant.

Skin Rashes, Eczema, or Other Skin Allergies

There was an overall excess of reporting of skin rashes, eczema, or other skin allergies in Benzene Subregistry population at Followup 4 compared with the NHIS population (O/E = 1.49, 99% CI = 1.08-2.01). There was also excess reporting by females in the age group 61 - 70.

Speech Impairment

Only one case of speech impairment was reported by Benzene Subregistry registrants at Followup 4, resulting in an overall SMR that was statistically significant lower than for NHIS.

Effects of Stroke

There was an overall excess of reporting of effects of stroke in the Benzene Subregistry population at Followup 4 compared with the NHIS population (O/E = 3.59, 99% CI = 1.65-6.74). An excess was seen for females in age group 31 - 40, based on three cases.

Ulcers, Gallbladder Trouble, and Stomach or Intestinal Problems

The 99% CI for the overall SMR included 1, indicating that reporting of this outcome by Benzene Subregistry registrants was not very different from that by the NHIS population

Urinary Tract Disorders, Including Prostate Trouble

The sex effect seen in the statistical model was due to excess reporting of urinary tract disorders by females (O/E = 9.12, 99% CI = 5.55-14.06). Excesses were found for females in the age group16 -23, 24 - 30 years, 31 - 40 , and 41 - 50.

SUMMARY

Statistically significant excesses were observed for anemia and other blood disorders; other respiratory allergies or problems, such as hay fever; skin rashes, eczema, or other skin allergies; effects of stroke; and urinary tract disorders, including prostate trouble. Table 9-4 summarizes of the statistically significant (p £ 0.01) risk ratios observed in Poisson modeling of Followup 4 data for health outcomes reported in excess. Results of health outcome comparisons, aggregated across age and sex, for all health outcomes reported by Benzene Subregistry registrants at Followup 4 are in Table 9-5.

SECTION 10: DISCUSSION

A key purpose of the Benzene Subregistry is to create a database that can be used to determine if there is an excess of adverse health conditions for registrants when compared with a national sample. To date, this objective has been pursued by comparing Benzene Subregistry data about reported health conditions with NHIS data. Health, demographic, occupational, and environmental information was collected on 1,143 benzene-exposed persons (1,127 living, 16 deceased). The analysis of the mortality data is not included in this report.

The registrants met the eligibility criterion of documented exposure. They resided for more than 30 consecutive days during the period of exposure at a site address known to have a contaminated water source, in this case, contamination with benzene. As is discussed in Section 2, the environmental data used was limited. Historically, the samples were not taken for the purpose of quantifying exposures over time. Rather, they were taken for the purpose of verifying the level of contamination at a past point in time. Regardless, the data serve the National Exposure Registry's purpose in that they establish that exposure to benzene occurred through use of contaminated water. Several sources of potential bias in the Benzene Subregistry population reporting rates were identified. One potential source of bias is nonresponse. However, the response rate of eligible persons who were located was 97%; such a high participation rate minimized or eliminated bias in the data that might have been associated with nonresponse. Another potential source of reporting bias is knowledge of exposure. Benzene Subregistry and NHIS data are similar in that both were self-reported; however, the responses of the registrants might have been influenced, in part, by their knowledge of and concern about benzene exposure. This potential bias has been examined (4); no definite increases in reporting due to knowledge of exposure were found.

The Subregistry and NHIS health condition questions, while sharing important similarities, differed in the restrictions on the source of diagnoses or treatment leading to a positive response to a health question. Also, there was a difference in the wording for some of the health questions. For those reasons, response rates may be altered or biased.

The comparability of the wording of Benzene Subregistry and NHIS health conditions was addressed in Section 3. Nine of the health condition questions matched exactly or very closely and eight others were considered similar. However, when the questions did not match exactly, again all other factors being the same, it was likely the dissimilarity would have resulted in decreased reporting by the Benzene Subregistry population in all categories save one-urinary tract disorders. The implications of health condition comparability are addressed further in the following discussion.

RECENT ADVANCES IN KNOWLEDGE ABOUT BENZENE TOXICITY

Benzene was selected as a primary contaminant for a subregistry in 1989. Since that time, additional information has been developed on the metabolism and toxicity of benzene for both humans and animals which is critical to understanding the potential for resulting health outcomes. The information available in 1989 is discussed in Section 2. The latter information is discussed here.

Absorption of benzene varies with route of exposure. In humans, respiratory uptake has been determined to vary from approximately 47% (21) to 80% (22), although dermal absorption can range from 0.05% to 0.2% (23). Absorption data for oral exposure in humans is not available; however, in animals, absorption rates following oral exposure to benzene we re found to be from 90% to almost 100% (24,25) and is vehicle-dependent.

Benzene must be metabolized to exert its toxic effects (26-35); however, this process is complex, consisting of multiple pathways (Figure 10-1). Benzene is metabolized by cytochrome P-450-dependent multifunction oxidase enzymes (36), with active oxygen species contribute to some extent to the toxicological properties of benzene's metabolites (37-43). A more in-depth discussion can be found in ATSDR (44).

Phenol, hydroquinone, and catechol are the major metabolites of benzene in mammals (45-48); however, these metabolites can affect each other's rate of metabolism because they are substrates for the same cytochrome P-450 enzymes (33,36,49). According to Cox (49), these interactions might help to explain the nonlinear relation between administered benzene concentrations and internal doses of metabolites. Indeed, it has been reported that a higher proportion of metabolites are produced at lower exposure concentrations (27,50-52), perhaps due to the possibility that benzene present in low concentrations is metabolized by the high affinity, ethanol-inducible isoenzyme CYP2E1 while benzene present in high concentrations is metabolized most significantly by the low affinity, phenobarbital-inducible isoenzyme CYP2B1 (56).

Sex differences are believed to play a role in the toxicity of benzene; however, the literature has been mixed. For example, Brown et al. (57) reported that women, who have a higher blood/air partition coefficient, higher maximum velocity of metabolism for benzene, and a higher body fat percentage than men are capable of metabolizing 23-26% more benzene than men when subject to the same exposure scenario even though benzene blood concentration levels are generally higher in men. In addition, a number of studies have reported the female to be more susceptible in both

Figure 10-1.—Scheme for metabolism of benzene. (Adapted from: 35,53-55).

humans (58-60) and animals (47,61-66). In contrast, male mice (67-69) have been reported to be more susceptible to benzene-induced chromosomal damage than are female mice. Still other studies (70-72) have found male and female humans to be equally susceptible to the effects of benzene exposure. It is important to note that the end points of these studies are variable.

The health effects of benzene exposure also depend both on the species exposed (31,73-75) and the route of exposure (49). All things being equal, humans tend to form lower internal doses of reactive metabolites than do animals (76); route of exposure has little or no effect on subsequent metabolism of benzene in humans (25,27,50,77). It should be noted, however, that Goldstein (78) postulated that humans might have a genetic predisposition to benzene toxicity. Finally, age can also play a role in metabolism of benzene, with younger animals displaying a higher rate of metabolism, and a greater susceptibility to toxic effects, than do older animals (79-81).

Following inhalation exposure, most benzene is excreted unchanged in exhaled air. Human excretion of absorbed benzene involves a biphasic urinary excretion (82) of conjugated derivatives (sulfates and glucuronides). Animal data show a similar pattern; that is, unmetabolized benzene is excreted primarily through exhalation, but metabolized benzene is excreted mainly in the urine (44). Benzene has also been detected in breast milk (83).

Ethanol has been shown to alter benzene metabolism. For example, ethanol has been shown to induce CYP2E1, a cytochrome P-450 enzyme responsible for benzene metabolism (36,84-87). Nakajima et al. (88) found that pre-exposure of male Wistar rats to ethanol not only increased the rate of metabolism of benzene by hepatic microsomes sixfold, but also significantly increased the rate of clearance of benzene from the blood. Ethanol has also been shown to enhance the toxicity of benzene in humans (89-92), as well as in animals (88,93-97).

Other substances may also affect the metabolism of benzene. Workers exposed to a combination of benzene and toluene produced significantly lower urinary phenol (a biomarker for benzene exposure) than those exposed to either benzene or toluene alone (98); toluene has also been shown to lower the toxicity of benzene in animals markers, or to detoxification, via pathways leading to mercapturic acid products and phenyl (99). It should be noted that Aroclor 1254 and phenobarbital are also known to alter the toxicity and metabolism of benzene (30,36).

Physiologically based pharmacokinetic (PBPK) models are used to allow interdose, interspecies and interroute pharmacokinetic extrapolation as well as prediction of target tissue exposure (100) and age-related changes in the disposition of benzene (101). According to Cox and Ricci (102), PBPK models are useful tools to use to correct risk assessments for nonproportional relations between administered and internal doses in test species; differences between routes of administration in terms of internal doses formed from a given amount of administered benzene; and interspecies metabolic differences in the production of external doses from administered doses. Several models are currently available (45,103-107); each varies in structure, the parameter values assigned, the data from which the values were derived, and metabolic constants. For discussions of these various models, the reader is referred to Bois et al., (108), Spear et al. (100), Cox and Ricci (102), and ATSDR (44).

HEALTH OUTCOMES

As discussed in Section 3, the comparisons of Benzene Subregistry and NHIS data on reported health conditions revealed several statistically significant differences. It should be noted that setting the Type I error (the α level) at £0.01 and the large sample size controlled the likelihood of false-negative or false-positive results. The results of the morbidity analyses are summarized in Table 10-1 and are discussed below with respect to the relevant literature.

Table 10-1.—Summary results of Benzene Subregistry-National Health Interview Survey comparisons for Baseline and Followups 1-4.

Disease Category	Interview Period
Disease Category	Baseline	Followup 1	Followup 2	Followup 3	Followup 4
Anemia	X	X	X	X	X
Arthritis		X
Asthma
Cancer	X	X	X	X
Diabetes				X
Hearing impairment
Hypertension
Kidney disease	X
Liver problems		X	X
Mental retardation
Respiratory allergies	X	X	X	X	X
Skin rashes	X	X		X	X
Speech impairment
Stomach, ulcers		X		X
Stroke		X	X	X	X
Urinary tract disorders	X	X	X	X	X

Anemia or Other Blood Disorders

The outcome anemia or other blood disorders was reported in greater numbers for the Benzene Subregistry population at all reporting periods. The excesses reported were: over at Baseline; those aged 46 through 65 years at Followup 1; overall and females aged 20 through 36 years and 57 through 66 years at Followup 2; overall and females aged 29 through 40 years at Followup 3; and all males and females at Followup 4. The questions for this outcome in the Benzene Subregistry and NHIS questionnaires were similar, but not a close match.

Benzene is a known hematopoietic poison and bone marrow depressant (75,78,108-113), having first been reported to produce anemia and leukopenia as long ago as 1897 (114). According to ATSDR (30), benzene was used at levels ranging from 43 to 71 milligrams per kilogram per day (mg/kg/day) as a treatment for leukemia before 1913. Case reports show the patients had decreased erythrocyte and leukocyte levels (115); however, it is uncertain whether these observations were a result of the disease or the treatment. Since that time, a variety of hematopoietic disorders, such as pancytopenia, aplastic anemia, preleukemia, leukopenia, acute myeloblastic anemia, thrombocytopenia, leukopenia associated with thrombocytopenia, nucleated red blood cells, and eosinophilia (30,36,47,49,92,116-130) have been associated with exposure to benzene. Myelofibrosis, a myeloproliferative disease in which the bone marrow is replaced with fibrous tissue, has also been associated with benzene exposure (131-137).

Worker studies have provided the basis for the description of hematologic outcomes in humans. Fishbeck et al. (138) reported that 282 workers exposed at a chemical factory to 25 ppm benzene for an average of 9 years and 7 months had an increased mean corpuscular level at the end of their high exposure period, but that levels had returned to normal 11 years later after exposure had ceased. Townsend et al. (139) reported slight decreases in red blood cell counts in this same population, but these decreases were not correlated with levels or durations of exposure (30). In a study of 459 workers in the rubber industry exposed to 15 to 75 ppm benzene from 1940 through 1975, decreased blood cell counts that did not persist when the exposure was decreased were reported; significant decreases in leukocyte and erythrocyte counts and hemoglobin were reported during the years of highest exposure (140). Doskin (141) reported lymphocytosis in workers exposed to 3 to 13 ppm benzene for 1 to 3 years. Finally, Midzenski and coworkers (92) reported that, of 15 workers acutely exposed over several days to high concentrations of benzene (>60 ppm), 9 had at least one hematologic abnormality consistent with benzene exposure. One year later, six workers (40%) had persistent abnormalities; six (40%) had numerous large granular lymphocytes on peripheral blood smears.

Aksoy and coworkers (142) followed the health of 217 male Turkish workers exposed to a maximum of 210 ppm benzene for a period of 4 months to 17 years and found leukopenia, thrombocytopenia, leukopenia associated with thrombocytopenia, pancytopenia, and eosinophilia. In a second study, Aksoy et al. (143) reported preleukemia and acute leukemia in 28,500 workers exposed to 210 to 650 ppm benzene for 1 to 15 years. It should be noted that the clinical features of preleukemia include one or more of the following: pancytopenia, bone marrow hyperplasia, pseudo-Pelger-Heut anomaly, and splenomegaly. Finally, of 44 pancytopenic patients followed postexposure, 23 went into complete remission; however, the others died from complications of the disease or from a successive blood disorder, such as myeloid dysplasia or leukemia (144).

Yin et al. (145,146) followed 528,729 Chinese workers, mainly from paint, shoe, rubber, leather, or adhesives factories, who were exposed to a range of benzene levels from <13 ppm (the majority) to 264 ppm. These workers reported leukopenia, aplastic anemia, and leukemia. The authors reported that these findings were similar to those of an additional 2,740 shoe factory workers they were also following. When following a cohort of 74,828 benzene-exposed and 35,805 unexposed workers employed between 1972 and 1987 in 12 Chinese cities, Yin et al. (72) found significant excesses for aplastic anemia (RR = infinity, 95% CI = 2.2-co) and myelodysplastic syndrome (RR = infinity, 95% CI = 1.7- infinity). In a follow-up study of this cohort, Linet et al. (147) found a diversity of malignant and nonneoplastic hematopoietic and lymphoproliferative disorders and excess myelodysplastic syndromes among benzene workers, as well as widespread dyspoiesis involving all hematopoietic cell lines among numerous patients.

A few cases of paroxysmal nocturnal hemoglobinuria (PNH) have been reported following benzene exposure (148-150). PNH is a chronic, acquired blood cell dysplasia in which there is a mutation of hematopoietic stem cells resulting in the production of erythrocytes, granulocytes, and platelets that are abnormally sensitive to complement lysis because of a lack of complement-inactivating proteins. PNH can occur concomitantly or sequentially in patients with aplastic anemia, or vice versa (150,151), and can also be a paraneoplastic disorder (78).

Considerable controversy exists as to whether low level exposures to benzene result in any measurable effects. Some studies of workers with lower benzene exposures (ie, lower than 25 ppm [152-154] or even levels below 10 ppm [154,155]) have shown abnormalities, whereas other studies have not (139,156). In a study of forty-nine benzene-exposed female workers and twenty-seven non-exposed controls in the shoemaking industry, Bogadi-Sare et al. (157) found that exposure to 1.9 to 14.8 ppm (5.9 median) benzene may produce qualitative abnormalities, particularly macroerythrocytosis and increased red cell glycerol resistance, in the absence of an overt quantitative decrease in circulating blood cells. On the other hand, Collins et al. (158) found no increase in the prevalence of lymphopenia (considered to be the earliest and most sensitive indicator of benzene toxicity) among 387 benzene-exposed workers (OR = 0.6, 95% CI = 0.2-1.8) vs. 553 unexposed workers, taking into account smoking, age, and sex. The daily 8-hour time-weighted benzene exposures averaged 0.55 ppm. Other measures of hematotoxicity, including mean corpuscular volume and counts of total white blood cells, red blood cells, hemoglobin, and platelets, also showed no significant changes.

Tsai and coworkers (159) reported no adverse hematologic effects in refinery workers exposed to low levels of benzene (less than 1 ppm) for 1 to 21 years. Wong (160) found substantially lower death rates for diseases of the blood in refinery workers in California when compared with workers with no occupational exposure to benzene. This result was confirmed in a followup of this cohort (161); however, neither study included women in most of the analyses and a strong "healthy worker" effect was believed to have played a significant role in the outcomes. In a study of 200 workers exposed to 0.01 to 1.40 ppm benzene per 8-hour time-weighted average for a 10-year period, Collins et al. (162) found no difference between the exposed workers and 268 nonexposed workers in the same plant.

Guiguet et al. (163) conducted a case-control study of new cases of aplastic anemia enrolled in a French national register of the disease. No differences were found between cases and controls for occupation, based on a 15-year occupational history, or for exposure to solvents. It should be noted, however, that a positive relationship between exposure to glues and paints-both of which could contain benzene-was found. The authors indicated that further investigation was needed for these relationships.

Animal studies have shown that chronic benzene exposure has a hematotoxic effect on hematopoietic stem cells, erythropoietic cells, and granulopoietic progenitors, as well as on erythrocytes and leukocytes (28,30,164-175). Using a mathematical model of murine hematopoiesis, Scheding et al. (176) found (1) erythropoietic cells were the most sensitive, (2) granulopoietic cells were about half as sensitive as erythropoietic, and (3) hematopoietic stem cells exhibited a sensitivity that ranged between that of erythropoietic and granulopoietic cells. It should be noted, however, that some reports on differentiated granulopoietic marrow and blood cells are ambiguous (94,95,165,167,176-179). Fetuses and offspring of pregnant mice exposed to benzene have also shown long-term functional changes in hematopoiesis (30,180,181).

Vacha et al. (182) reported that ferrokinetic indicators of benzene-exposed mice showed only a slightly enhanced production of heme and erythrocytes in the spleen; however, the life spans of late erythroblasts and circulating erythrocytes were reduced. Low-molecular-weight bleomycin- detectable iron was also observed in the bone marrow following administration of benzene to female rats (183). The authors suggested that the accumulation might lead to the formation of tissue-damaging species, such as lipid peroxide radicals or superoxide anions.

In other animal studies, Aoyama (184) exposed mice to 200 ppm benzene for 6 hours per day for 7 days or 50 ppm for 14 days. He reported that the mice had decreased levels of white blood cell counts in both the blood and spleen. Similar results (decreasing circulating leukocytes) were seen for rabbits, rats, and guinea pigs (28,169,185,186) following various exposure scenarios. Rats (187) and mice (166,167,171,187-189) were also found to have leukopenia, but in conjunction with anemia, following various exposure scenarios. Finally, mice exposed to 300 ppm benzene for 6 hours per day, 5 days per week, for 16 weeks were found to have granulocytic hyperplasia in the bone marrow (190).

Negative results have also been reported for animal studies. Deichmann et al. (191) found no effects in rats exposed to benzene levels <31 ppm for 7 hours per day, 5 days per week, for 88 to 126 days. Jenkins et al. (192) found no hematologic effects in rats, guinea pigs, or dogs exposed continuously to 17.6 ppm benzene for up to 127 days. Svirbely et al. (193) exposed rats to 1,000 ppm benzene for 7 hours per day, 5 days per week for 28 weeks and found only a very slight reduction in white cells counts, but no overt signs of toxicity. Other animal studies also reported negative results following benzene exposure (194-196).

It has long been recognized that animal responses to benzene are varied and can depend on factors such as species, strain, duration of exposure, and route of exposure (continuous or intermittent) (31,73,165,191,197-199). Effects reported include anemia (166,168,200) and bone marrow abnormalities (168,201), as well as the previously mentioned abnormalities in the numbers of specific cell types (164,166-168,172,173,175). Depression of lymphocytes and nucleated red cells formed in the spleen have also been noted in mice (155). Snyder et al. (165) reported that mice chronically exposed to benzene intermittently over their lifetime developed bone marrow hypoplasia and pancytopenia (30).

As stated previously, the hematotoxic effects of benzene are increased by ethanol. This has been demonstrated for blood cell counts and bone marrow cellularity in mice and rats (88,93,94,199) and for the hemopoietic progenitors (96). It can be seen that the combination of ethanol and benzene leads to the same effects as an increase in the benzene dose or a prolongation of the exposure period. Of particular interest is the reported transient appearance of nucleated red cells (normoblasts) in the circulating blood of animals exposed to benzene and ethanol. It has been shown that the bone marrow is the source of these normoblasts, because the cells also appear in the circulating blood of exposed, splenectomized animals (95,97).

Several authors have reported recovery of hematopoiesis following termination of chronic benzene exposure (97,165-167,174,175,202). These studies have shown that hematopoietic stem cell recovery is rapid and complete for short exposure periods (less than 8 weeks); however, longer exposure periods result in a considerable delay in stem cell recovery, indicating a benzene-induced residual hematopoietic injury (167,176). Following in vivo hemin treatment, Abraham (203) reported a strong, long-lasting toxic effect on the bone marrow stroma with only limited recovery.

It is believed by many investigators that the myelotoxic (marrow damaging) and hematotoxic (blood-system damaging) effects of benzene are probably mediated by the interactions of two or more benzene metabolites with each other and with target cells in the bone marrow (see Figure 10-2) (26,42,49,130,155,180,202,204-220). The effects seen include delay of bone marrow cell life cycles and change of mitotic indices; killing of stem cells in specific phases of the cell life cycle; inhibition of cellular functions; and damage to the stromal microenvironment that normally regulates stem cell proliferation and differentiation. These cytotoxic effects have been demonstrated experimentally (49,130,188,220,221). Niculescu and Kalf (222) have reported that interleukin-1 alpha (IL-1α), when added concomitantly with benzene, will prevent benzene-induced depression of bone marrow cellularity as a function of dose; however, it has been demonstrated that benzene can interfere with the production of IL-1α (223). Benzene metabolites interact strongly in inhibiting the growth and functioning of erythrocytes (224). This interaction has been demonstrated in a study by Snyder et

Figure 10-2.—Schematic of blood cell differentiation and maturation.

al. (211), in which benzene suppression of erythropoiesis was measured by the uptake of radiolabeled iron into the red blood cell hemoglobin of female mice, and in a study by Dempster and Snyder (202), in which short-term benzene exposure induced a growth advantage for granulocytic cells in both the bone marrow and spleen of exposed mice.

The ability of benzene metabolites to suppress lymphocyte growth and function in vitro correlates both with their oxidation capacity and with their concentration at the target site (99,225-229). For example, hydroquinone and benzoquinone inhibit proliferation and differentiation in lymphocytes in culture at noncytotoxic concentrations; phenol or catechol suppress lymphocyte growth or function at concentrations that result in cell death (99). In addition, hydroquinone and catechol have been shown to reduce the number of spleen and bone marrow progenitor B lymphocytes and to inhibit polyclonal plaque-forming cells (99,230).

Benzene affects macrophages as well as lymphocytes (207,212,222). According to Cox (49), experiments with cultured macrophages have shown that benzene metabolites are effective inhibitors of hydrogen peroxide releases from stimulated macrophages. (Note: The release of hydrogen peroxide normally allows macrophages to kill invading bacteria and other threats.) In addition, p-benzoquinone inhibits phagocytosis and cytolysis of tumor cells by macrophages.

There is considerable evidence supporting the hypothesis that p-benzoquinone is a major source of benzene health effects (26,31,46,49). Both hydroquinone and p-benzoquinone (as well as catechol and 1,2,4-benzenetriol at higher concentrations) reduce the ability of the stromal microenvironment to support granulocyte or macrophage stem cell formation in vitro (75,220). Benzene exposure decreases the subsequent ability of the marrow-adherent layer of stromal cells to support normal stem cell differentiation in vitro (26,231).

In view of the reported literature, it is possible that chronic exposure to benzene in the environment can result in blood disorders. As mentioned earlier, some researchers have reported that a higher proportion of the toxic metabolites of benzene are produced at lower exposure concentrations (27,51,52), a phenomenon that might have played a role in the trends reported here. In addition, excess reporting has occurred mainly for females, indicating a greater susceptibility to benzene intoxication, as has been indicated by some researchers (47,58,60-63,65,66).

Arthritis, Rheumatism, or Other Joint Disorders

There was an increase in Benzene Subregistry registrants' reports of arthritis, rheumatism, or other joint disorders in the 1 through 10 years of age group compared with those of the NHIS population at Followup 1. The reports of this outcome were significantly reduced overall at Baseline and Followups 2 and 3, as well as for those registrants aged 26 through 45 years at Followup 1. As discussed earlier, arthritis, rheumatism, and other joint disorders are conditions that are likely to be self-diagnosed, and, therefore, increased reporting by the NHIS population would be expected. The Subregistry and NHIS questions for this outcome were similar, but not a close match.

No studies were located specifically addressing the potential effects of benzene on the development of arthritis, rheumatism, or other joint disorders in either humans or animals. There have been reports, however, of skeletal malformations in the offspring of benzene-exposed animals. Benzene can cross the placental barrier and is found in cord blood at levels equal to or greater than those observed in the mother (232); thus, the fetus might be exposed to relatively high levels of benzene and its metabolites. In one study, Murray et al. (196) observed offspring of CF-1 mice and those of New Zealand rabbits. Mice exposed to 500 ppm benzene for 7 hours per day on days 6 through 15 of gestation had offspring with mean fetal body weights that were significantly lower (p < 0.05) and minor skeletal variants-delayed ossification-that were significantly greater than those of controls. The variants were considered to be indicative of delayed development, but not of major malformations. The rabbits were exposed in a similar manner but their offspring demonstrated no treatment-related effects.

In another study, pregnant Sprague-Dawley rats were exposed to 0, 10, 50, or 500 ppm benzene for 7 hours per day on days 6 through 15 of gestation (233). Offspring of the 500 ppm group had significantly reduced mean crown-to-rump length, reduced fetal body weight, and delayed ossification. Four of the offspring from this group had skeletal anomalies-exencephaly, angulated ribs, and out-of-sequence ossification of the forefeet. Offspring of the 50 ppm group also demonstrated reduced fetal body weights and delayed ossification; no other differences were reported for this group or the remaining groups.

In a similar study, Green et al. (234) exposed Sprague-Dawley rats to 100, 300, or 2,200 ppm benzene for 6 hours per day on gestation days 6 through 15. A significant decrease in mean fetal weight was reported for the 2,200-ppm group; decreased crown-to-rump length was also significantly reduced in this group. Female offspring in the 300 and 2,200 ppm groups displayed significantly increased delayed ossification of sternebrae; this effect was not seen for the males. In addition, only the females in the 2,200 ppm group had an increase in missing sternebrae. Other studies have also reported skeletal variations following benzene exposure during gestation, including cleft palate, agnathia, and micrognathia (235) as well as extra ribs and fused sternebrae (236).

Similar studies reporting negative results were also found. Nawrot and Staples (237) administered 0.3, 0.5, or 1.0 mg/kg/day to pregnant CD-1 mice by means of gavage on gestation days 6 through 15. Even at the highest dose level there were no statistically significant changes in the incidence of malformations. No malformations were seen in offspring of mice exposed to 156.5 or 313.0 ppm benzene for 12 hours per day on gestation days 6 through 15 (238). No skeletal variants were reported by other researchers in similar studies with rats (239,240) or cultured rat embryos (241).

Cancers

Participants in the Benzene Subregistry reported more cancer overall at Baseline and Followups 1 through 3 than participants in the NHIS. The Subregistry and NHIS questions were similar, but not a close match.

Benzene exposure, and its association with cancer, has been extensively covered in the literature. There is sufficient evidence to have declared benzene a carcinogen (113,121,122,242). Many authors (26,49,106,216,231,243) and reviews (149,244) have demonstrated that the metabolites of benzene are primarily responsible for the carcinogenic action of benzene. According to Cox (49), benzene metabolites are responsible for the progression of a malignant clone of cells from a few (possibly dormant) transformed cells to a clinically detectable neoplasm by means of (1) deregulation of cell differentiation from toxic damage to the bone marrow stromal microenvironment (212); (2) suppression of immune surveillance by toxic metabolites, making it easier for malignant cells to survive and proliferate (207); or (3) inhibition of proliferation of normal cells by differential cytotoxicity compared with malignantly transformed cells (49).

Smith (245) has proposed an overall hypothesis for benzene-induced leukemia that includes the generation of active oxygen species via redox cycling resulting in damage to tubulin, histone proteins, topoisomerase II, other deoxyribonucleic acid (DNA) associated proteins, and DNA itself with consequent damage including DNA strand breakage, mitotic recombination, chromosome translocations, and aneuploidy. As seen with Cox (49), Smith (245) proposes that the epigenetic effects of these metabolites on the bone marrow stroma may then foster development and survival of the malignant cells.

Benzene affects macrophages as well as lymphocytes. Experiments with cultured macrophages have shown that hydroquinone, p-benzoquinone, and catechol are all highly effective inhibitors of hydrogen peroxide release from stimulated macrophages (>90% reduction for concentrations of 15 micromoles [μM] for all three metabolites). The release of hydrogen peroxide normally allows macrophages to kill invading bacteria and other threats. P-benzoquinone also inhibits phagocytosis and cytolysis of tumor cells by macrophages at concentrations of >10 μM (207). 1,4-Benzoquinone was also found to be the most potent metabolite in reactive oxygen species formation, which is believed to be a mechanism in the induction of leukemia (246).

Chronic exposure to benzene has been demonstrated to cause leukemia in humans (30,58,78,113,120,129,142,216,247-251). The types of leukemias and lymphoproliferative diseases known or believed to be caused by benzene exposure are acute myelogenous leukemia, acute lymphocytic leukemia, acute erythrocytic leukemia, acute myelomonocytic leukemia, acute promyelocytic leukemia, acute undifferentiated leukemia, hairy cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and multiple myeloma (118,124,202,210,252-265). The most common type of leukemia among individuals chronically exposed to benzene is acute myeloblastic leukemia (261), a disease characterized by a proliferation of cells morphologically indistinguishable from myeloblasts.

Numerous epidemiologic studies and case reports (49,117,118,123,124,127,142-146,160, 161,252,254,262,266-274) have demonstrated a causal relationship between benzene exposure and leukemia in occupationally exposed workers. These studies include roughly 28,500 Turkish shoe workers (average daily dose estimated from 210 to 650 ppm) among whom Askoy (118) identified a statistically significant number of leukemia cases.

Yin et al. (146) reported 30 leukemia cases observed among 28,460 benzene-exposed Chinese workers whose average daily dose was estimated at over 100 ppm. In preliminary analyses, the leukemia rate in Chinese workers was about twenty-fold higher for those having benzene exposure (271). In a follow-up report, deaths due to all hematopoietic and lymphoproliferative malignancies (p = 0.01) and lung cancer (p = 0.01) were increased among workers with greater cumulative exposures (275). In a further analysis, Yin et al. (72) reported statistically significant excess deaths for leukemia (RR = 2.3, 95% CI = 1.1-5.0) and malignant lymphoma (RR = 4.5, 95% CI = 1.3-28.4). Among the leukemia subtypes, only acute myelogenous leukemia incidence was significantly elevated (RR = 3.1, 95% CI = 1.2-10.7), although nonsignificant excesses were also noted for chronic myelogenous leukemia and lymphocytic leukemias. When looking at the same cohort, Hayes et al. (276) found the RR for all hematologic neoplasms combined among workers who were occupationally exposed to benzene to be 2.6 (95% CI = 1.4-4.7) while the RR for all hematologic neoplasm combined was 2.2 (95% CI = 1.1-4.2), and, for the combination of acute nonlymphocytic leukemia and related myelodysplastic syndromes, the RR was 3.2 (95% CI = 1.0-10.1) among workers historically exposed to benzene at average levels of less than 10 ppm. For individuals exposed to higher concentrations (constant levels of 25 ppm or more), the RR for the combination of acute nonlymphocytic leukemia and related myelodysplastic syndromes was 7.1 (95% CI = 2.1-23.7). Li et al. (70) reported similar findings for 74,828 benzene-exposed workers compared with 35,805 unexposed workers from 12 cities in China; in addition, no significant differences in the relative risks for total mortality and cancer mortality were found between female and male benzene-exposed workers. These results corroborated their previous findings (71). Leukemogenic effects were also reported in the Pilofilm (rubber) worker population (124,252,254,272,277-279).

There have been a number of studies implicating exposure to benzene or benzene-containing products with the development of leukemia in children. In a highly controversial report, Knox (280) found the occurrence of childhood leukemia to be associated with the use of petroleum. After this report was challenged (281), Knox and Gilman (282) expanded the study to include 22,458 children 0 to 15 years of age who had died from leukemia or other cancer in England, Wales, or Scotland between 1953 and 1980. They concluded that childhood cancers were at least partially associated with benzene-containing products such as petroleum-derived volatiles and effluents from internal combustion engines. It should be noted that there are reports of the occurrence in young children of acute monoblastic leukemia that appear to be associated with parental exposure to pesticides, solvents, and petroleum products (283-289). Feingold et al. (270) examined the association between parental occupational exposure to benzene and childhood cancer. They found elevated odds ratios for maternal exposure and for paternal exposure to benzene in relation to total cancers in their offspring. Control for other potential childhood cancer risk factors did not alter the results substantially. The authors believed their findings of a suggested association with parental benzene and petroleum exposure corroborated similar observations by Shu et al. (285). The entire issue of childhood cancers and exposure to environmental toxins remains highly controversial.

In an ecological study in which both gasoline consumption data and data on leukemia mortality and incidence were collected for 19 European countries, Swaen and Slangen (250) found a weak inverse association between temporal trends in gasoline consumption and temporal trends in leukemia mortality and a weak positive association between the age-adjusted myeloid leukemia incidence in 14 areas and the gasoline consumption per square kilometer. The authors cautioned that their findings could be explained by other factors, such as differences in leukemia case ascertainment. Van Raalte (290) reported similar findings. Wolff (265), however, reported a statistically significant association between automobile ownership and acute myeloid leukemia, as well as between all lymphoproliferative diseases and automobile ownership. His findings are in agreement with those obtained by Robinson (291) who showed a strong relationship between Australian leukemia mortality and vehicle usage. A study of childhood leukemia incidence in Denver, Colorado, indicated that rates of leukemia were higher in areas of higher traffic density (292); this finding also potentially supported Wolff's findings. Alexander et al. (293), however, found no association between car ownership and acute lymphocytic leukemia in children.

In a retrospective follow-up study of 594 chemical workers occupationally exposed to benzene, which was expanded and updated in 1986 (268), Ott et al. (266) reported an incidence rate ratio of 4.4 (1.2-11) for myelocytic leukemia for benzene-exposed workers relative to the general population. A cohort mortality study of 4,172 chemical plant workers reported elevated rates of leukemia (SMR = 2.3, 95% CI = 0.7-5.3) and multiple myeloma (SMR = 2.3, 95% CI = 0.7-9.4) among production workers with benzene exposure, predominantly among those whose exposures were 20 or more years prior to the onset of disease (294). Other worker studies (134,255,267,295-304) generally confirmed these findings.

Unfortunately, there are few data from which dose-response relationships can be established because of the deficiencies in the clinical and epidemiologic studies-such as the lack of appropriate sampling techniques, incomplete exposure determinations, lack of followup, and weak experimental designs or methodology-as well as the intermittent exposures to benzene, which make it difficult to assume that the average concentrations of benzene measured in a workplace actually indicate the true exposure experienced by each worker (109). Indeed, there are reports of a negative relationship for benzene and leukemia. For example, Hurley et al. (305) reported that male industrial workers employed in 1967 in self-contained coke works or coke departments had no excess mortality from leukemia. Another epidemiologic study of Texas refinery workers showed no leukemia deaths from benzene exposures that were <1 ppm (159). In an update of the Texaco mortality study, Divine et al. (306) reported no increases in leukemia mortality for the total cohort, and that a cell type analysis of leukemia mortality for the total cohort also showed no significant increases for the major cell types, although there were significant increases for acute unspecified leukemia (SMR=276) and leukemia of unknown cell type (SMR=231). In a meta-analysis of all cohort studies of petroleum workers in the United States and the United Kingdom (over 208,000 petroleum workers, contributing more than 4.6 million person-years of observation) Raabe and Wong (307) found no increases in acute myeloid leukemia (meta-SMR = 0.96), chronic myeloid, acute lymphocytic, or chronic lymphocytic leukemias (meta-SMRs of 0.89, 1.16, and 0.84, respectively). In addition, stratified meta-analyses restricted to refinery studies or to studies with at least 15 years of follow-up yielded similar results. These findings were supported by Wong et al. (308). Finally, in an analysis of published case series and epidemiological studies through mid-1995, Bezabeh et al. (309) found that the literature indicated benzene exposure was not a likely causal factor for multiple myeloma. This finding was supported by a meta-analysis of 22 cohort mortality studies of petroleum workers in the United States, the United Kingdom, Canada, and Australia in which no increased risk of multiple myeloma was found as a result of exposure to benzene (310).

Exposure to benzene or mixtures containing benzene have also been implicated in causing other types of cancer in humans. These cancers include bladder, stomach, prostate, and lung neoplasms (122,311-316), primarily observed in rubber workers. In a study of 3,473 Russian women employed in the printing industry, Bulbulyan et al. (317) found a significant excess of esophageal cancer, based on seven deaths (E = 2.7, SMR = 2.7, 95% CI = 1.1-5.4). The SMRs were higher among bookbinders and women hired before 1957 (the last year benzene was used in bookbinding). In this study, press operators also had significantly elevated mortality from stomach, cancer (O = 9, E = 4.1, SMR = 2.2, 95% CI = 1.0-4.2). Stomach cancer was also reported for shoe workers (304).

In 1989, Steineck et al. (318) observed a small increase in the risk of urinary bladder cancer after exposure to benzene. These results were reported to be similar to those of Wong (319), who observed two cases of urinary bladder cancer among workers exposed from 5 to 14 years to benzene and two cases among workers exposed 15 years or more. In a historical cohort study of 2,008 Italian shoe workers, Fu et al. (304) found some evidence for an excess of bladder cancer. Finally, in a population-based case referent study of urothelial cancer, Steineck et al. (320) reported that exposure to benzene (any annual dose) gave a relative risk of 2.0 for development of urothelial cancer; however, the authors concluded that the determination of a cause-and-effect relationship was confounded by exposure to other chemicals in addition to benzene.

In Russia, ovarian cancer was found to be significantly elevated among bookbinders (O = 12, E = 4.2, SMR = 2.9, 95% CI = 1.5-5.0), although the greater risk was observed among women hired after 1957 (the last year benzene was used in the process) (O = 5, E = 1.2, SMR = 4.8, 95% CI = 1.5-11.1) than among women hired before 1958 (O = 7, E = 3.7, SMR = 1.9, 95% CI = 0.8-3.9) (317). The risk of ovarian cancer was also higher for women employed 15 or more years (O = 7, E = 2.0, SMR = 3.5, 95% CI = 1.4-7.1) than for women employed 2 through 14 years (O = 5, E = 2.7, SMR = 1.9, 95% CI = 0.6-4.3).

In a case-referent study of premenopausal breast cancer and occupational exposure to benzene, Petralia et al. (321) found a dose-response relationship for the probability of exposure to benzene at both low probabilities (OR = 1.64, 95% CI = 0.64-4.21) and high probabilities of exposure (OR = 1.95, 95% CI = 1.14-3.33). Risk increased with duration of exposure to benzene, but no dose-response relationship could be determined. Although one-half of the benzene-exposed women were also exposed to polycyclic aromatic hydrocarbons (PAH), when women who had PAH exposure were excluded, exposure to benzene for at least 4 years was associated with a 3-fold increase in risk. Other studies of benzene exposure and breast cancer have been both positive (322) and negative (126,323).

In the study of Chinese workers exposed to benzene, Yin et al. (146) reported significantly elevated SMRs for lung cancer and nonstatistically significantly elevated SMRs for primary hepatocarcinoma and stomach cancer. It should be noted, however, that the authors cautioned that the estimated average and cumulative lifetime benzene exposure levels were based on relatively few measurements. Among Turkish workers, benzene exposure was related to the development of other forms of cancer, such as lung cancer (247,248). Dagg et al. (161), however, found significantly lower rates of lung cancer among a cohort of 14,074 refinery workers.

A few studies (324-326) have reported nonsignificantly elevated risks of developing soft tissue sarcoma (STS) in benzene-exposed workers. It should be noted that both misclassification of STS and the small numbers of cases often are problematic for interpreting these studies.

Reports of the risk of developing renal cancer following benzene exposure have been negative. Enterline and Viren (327) reviewed the epidemiologic evidence for an association between petrol (gasoline) exposure and kidney cancer and concluded that there was little support for an etiologic link in the 12 cohort, 3 case referent, and 3 ecologic studies included in their review. Similar conclusions had been reached in a workshop on the subject a year earlier (328,329) and in a 1987 review of several cohort studies examining the relationship between organic solvents and renal cancer (330). Four additional studies (308,331-333) also found no relationship between exposure to solvents and renal cancer. Only one study, Fu et al. (304), indicated a potential for development of kidney cancer following exposure to benzene.

Multiple studies (28,30,31,47,165,167.169,188,334-344) have demonstrated that benzene is a multisite carcinogen in animals. Cancer sites reported have included the nasal and oral cavity; lung; forestomach; liver; skin; zymbal, mammary, Harderian, and preputial glands; ovary; and uterus. Lymphoma, hemolymphoreticular neoplasia, and all types of leukemias have also been reported in animals. For leukemogenicity, as opposed to cytotoxicity, there is some evidence that lifetime exposure to benzene in animals might actually suppress the development of leukemia-presumably because of the cytotoxic effects that prevent potentially leukemic cells from surviving and expressing themselves-but a much shorter (16-week) exposure period dramatically increases the incidence of myelogenous and other neoplasms (49,188). Metabolites of benzene, including hydroquinone, catechol, and p-benzoquinone, have been reported to damage or suppress the activities and levels of various white blood cells in the immune system, leaving the exposed animal vulnerable to both bacterial pathogens and to transplanted tumor cells (49,207).

Cancer is caused by genotoxic events in somatic cells (47); benzene is also a known genotoxin. Cytogenetic studies in benzene-exposed workers have shown that exposure to benzene is associated with frequencies of both structural and numerical chromosomal aberrations (30,121,122,152,216,261,345-353). For example, significant increases in dicentric chromosomes and sister chromatid exchange (SCE) frequencies were reported among benzene-exposed females in the Croatian shoe industry (351); significant increases of single strand breaks were reported in men occupationally exposed to benzene from gasoline (354); and significantly increased rates of loss and long arm deletions of chromosomes 5 and 7 among benzene-exposed workers in Shanghai, China (355,356). The limitations of occupational studies, including a lack of accurate exposure data, possible coexposure to other chemicals, and selection of appropriate control groups must be considered when interpreting the data from such studies.

Currently many investigators believe that two or more benzene metabolites might be responsible for the myelotoxic and genotoxic effects of benzene (54,210,213,214,216,217,219,224,356,357). Epigenetic effects have also been proposed to contribute to the toxicity of benzene (37,219,358-365).

Benzene crosses the placenta and is found in cord blood in amounts equal to or greater than those in the maternal blood (232). Funes-Cravioto et al. (1345) examined genetic outcomes in children of female workers exposed by inhalation to benzene and other organic solvents during pregnancy. They found increased frequency of chromatid and isochromatid breaks and SCE in the lymphocytes of these children.

Negative results have been reported concerning chromosomal aberrations following benzene exposure in humans (366). Yardley-Jones et al. (156), Seiji et al. (367), and Xu et al. (368) investigated SCEs in humans and found negative results. Sarto et al. (369), Watanabe et al. (370), and Bukvic et al. (371) also did not find raised SCE frequencies following exposure to benzene; Clare et al. (372) reported an insignificantly raised SCE frequency after acute exposure to high benzene concentrations during one shift. Hallberg et al. (373) found a lack of significant differences in DNA repair capacity between benzene-exposed and control workers; however, the authors believed this finding to be due to an extremely low exposure to benzene (<0.3 ppm), the small population size, or a lack of benzene genotoxicity at these concentrations. Reports of studies of micronucleus frequencies in human lymphocytes have all been negative (371,374).

Data from animal studies provide convincing evidence that benzene and its metabolites are genotoxic (26,30,65,66,211,213,214,216,224,375,376). Positive results have been reported from analyses of chromosomal aberrations, SCE, and micronuclei in the bone marrow, lymphocytes, erythrocytes, and lung fibroblasts of rats, mice, and rabbits (30,49,65,66,69,113,121,122,172,173,201,376-382). Other evidence of genotoxicity induced by benzene includes inhibition of DNA synthesis (383) and delayed cell cycle in mouse bone marrow and DNA adducts with benzene metabolites in mouse and rat hemoglobin or rat liver cells (30,51,377,378,384-386).

Several studies (387-390) have reported no increased strand breakage in vitro related to benzene exposure; however, metabolic activation of benzene or treatment with benzene metabolites has led to increased DNA strand breakage (208,348,378,389,391-395).

Benzene was not mutagenic in a range of bacterial and yeast systems (113,396-400), including the conventional Ames test (401). It was, however, found to be mutagenic in a sensitive microsuspension assay using the Salmonella strain TA 100 (402) and to produce positive responses in repair-deficient strains of Escherichia coli and Bacillus subtilis (403,404).

Results of animal studies investigating benzene as a transplacental genotoxic agent have been varied. Xing et al. (381) reported that benzene caused a significant increase in micronuclei and SCE in both maternal bone marrow and fetal liver cells of mice. This result was consistent with that reported by Sharma et al. (405) and Ning et al. (113). Contrary to the positive findings, Harper et al. (380) reported that benzene caused almost no response in either pregnant female or fetal mice at a single oral or injected dose.

Cardiovascular Outcomes (Hypertension and Effects of Stroke)

No statistically significant results were seen for registrants for hypertension at any interview; however, the effects of stroke were significantly increased overall at Followups 2 through 4, for those aged 26 through 35 years at Followup 1, for females aged 27 through 36 years at Followup 2, and for females aged 31 through 40 years at Followup 4. The NHIS and Subregistry questions for hypertension and effects of stroke are both a close match.

There are few reports in the literature of cardiovascular problems following benzene exposure, even though it has been suggested that severe, acute benzene poisoning can result in direct myocardial damage (406), including fragmentation and waviness of cardiac myofibrils (407). Yin et al. (71) reported that cardiovascular disorders were the second most common cause of death among benzene workers. Zoloth et al. (131) found a significantly elevated risk of arteriosclerotic heart disease (PMR = 113) in a working population exposed to benzene and other solvents. Lloyd et al. (408) also found increased mortality due to heart disease in a similar worker population.

Case reports of cardiovascular problems following benzene exposure were more commonly found. Avis and Hutton (409) found ventricular fibrillation to be the cause of death for three people having acute benzene poisoning resulting from an industrial accident aboard a chemical cargo ship. In addition, the brain of each individual appeared grossly normal but showed microscopic evidence of prominent vascular congestion on autopsy. Harada et al. (407) reported hyperpermeability of blood vessels in the brain of a young woman who had committed suicide by ingesting benzene. According to Fielder and coworkers (410), the postmortem findings for a number of fatalities attributed to the inhalation of high concentrations of benzene included extensive petechial hemorrhages in the brain and pericardium. These findings are similar to the autopsy finding of cerebral edema reported by Winek and Collom (411) and Barbera et al. (412). Davies and Levine (149) reported on two series of case studies in which arterial hypertension was cited as an outcome of benzene exposure. These studies included one by Reznik in 1974 in which arterial hypertension was reported in 150 patients with a 15- to 26-year history of chronic poisoning with benzene derivatives. Of the exposed individuals, 52% had either arterial hypertension or arterial pressure within the limits of a "transition zone" (undefined). Davies and Levine (149) also reported that in 1979 Karmaz found hypercholesterolemia and hyperphosphatidemia in 250 workers employed in coke-benzene production.

Negative reports of cardiovascular problems following benzene exposure were also found. For example, Dagg et al. (161) found significantly lower rates of heart disease and other conditions in a worker population.

Sudden deaths from cardiovascular problems, predominantly ventricular fibrillation, have also been observed in laboratory animals following acute benzene poisoning (64). For example, Nahum and Hoff (413) reported extra systoles and ventricular tachycardia of the prefibrillation from electrocardiograms of cats and monkeys, which reflected the effects of acute benzene inhalation exposure on the heart muscle. Moravi et al. (414) found that rats exposed to benzene invariably exhibited ventricular fibrillation following respiratory arrest. Finally, Vidrio et al. (415) and Magos et al. (416) found that benzene increased the arrhythmogenic action-specifically ventricular arrhythmias-of epinephrine in rats exposed to 3,526 to 8,224 ppm benzene.

Diabetes

Diabetes was reported in excess for males and females 59 through 68 years of age at Followup 3. Also notable is that at many time periods the rates were elevated but not statistically significant. The NHIS and Subregistry questions for diabetes were an exact match.

Few studies mention diabetes in humans as a potential outcome of benzene exposure. In a survey of dry-cleaning workers in Nagoya City, Japan, Takeuchi and coworkers (417) found one case of diabetes mellitus among workers in one shop who were directly engaged in dry cleaning using a mixture of petroleum solvents and tetrachloroethylene. In a mortality study of refinery workers in California, Wong (160,319) found substantially lower death rates from diabetes, a finding that was confirmed in an update of the cohort (161). It should be noted that both of these studies excluded women from most of the analyses and that the authors believed a strong "healthy worker" effect was responsible for much of the outcome.

Diabetes is a chronic syndrome of impaired carbohydrate, protein, and fat metabolism secondary to insufficient secretion of insulin or target tissue insulin resistance that results in elevated blood glucose levels. There are two major types of diabetes: insulin-dependent diabetes mellitus (IDDM or type I), in which exogenous insulin is necessary, and non-insulin-dependent diabetes mellitus (NIDDM or type II), in which exogenous insulin is not required. Although IDDM can occur at any age, peak onset is 12 years of age. NIDDM typically occurs after 40 years of age, with peak onset occurring from 50 to 60 years of age. Because the excess of diabetes reported for the Benzene Subregistry occurred in the group aged 10 to 17 years, it is likely that IDDM is the type of diabetes most prevalent; therefore, the discussion that follows focuses on this type of diabetes.

The most generally accepted hypothesis of IDDM pathogenesis follows this course: genetic susceptibility ® environmental trigger ® immunological activation ® progressive beta cell (pancreas) destruction ® abnormalities of insulin secretion ® early metabolic abnormalities ® onset of symptoms (418). Although there are genetic markers highly associated with the incidence of IDDM (for example, the non-Asp-57 marker), fewer than 3% of the people within a population who have such a genetic marker develop the disorder. Almost all people who develop IDDM have the marker and only a very small percentage having the marker will develop the disease, presumably because of the interaction of host and environmental factors. It might be suspected, therefore, that the susceptible people who develop diabetes have been more exposed than those who do not develop this disease (419).

Although genetics has been demonstrated to play a major role in the development of IDDM, it cannot explain all cases, which strongly suggests that an environmental influence is superimposed on the heritable component of IDDM (420). Indeed, at least one study (421) has suggested that sibling pairs are more likely to have onset of diabetes within a year of one another than would be expected by chance. As noted previously, two of the cases of diabetes reported for the Benzene Subregistry were those of siblings. A similar observation of clustering of time of onset seems to occur in the monozygotic twins of diabetic parents (422). Goldstein (125) has also suggested that there might be a genetic predisposition to benzene toxicity. This evidence can be interpreted as suggesting a common exposure to an agent that either initiates or precipitates IDDM (423). In addition, the stability of the annual incidence of IDDM implies a comparable stability in the prevalence of the causal environmental factor, which is uncharacteristic of most viruses and bacteria (421).

According to the World Health Organization DIAMOND Project Group on Epidemics, a major difficulty in the area of IDDM research-despite strong epidemiologic evidence that environmental agents are potent causes of IDDM (424)-is that the identification of such agents has been elusive. It is noteworthy that several recent epidemiologic studies have reported that the incidence of IDDM is increasing, suggesting that long-term changes in the environment are altering the probability of eventual diabetes.

According to Palmer and Lernmark (425), the possible environmental mechanisms involved in the development of IDDM include causing direct toxicity to beta cells, triggering of an immune reaction against beta cells, inducing increased insulin need that cannot be met by damaged beta cells, and altering beta cells to increase susceptibility to damage. Conditions and syndromes associated with IDDM include pancreatic disease from trauma, infections, toxic injury, neoplastic conditions, hormonal disorders (such as hypothalamic lesions), and neurologically active agents (such as epinephrine), as well as post-infancy-acquired pancreatic disease (425,426). Several epidemiologic studies have reported an excess of pancreatic cancer for individuals following exposure to benzene (131,408,427,428). In animals, Yang et al. (429) reported that benzene-treated animals altered pancreatic excretion by increasing the flow by more than 900% and by reducing the protein concentration of the pancreatic fluid by more than 50%. The pancreas was not assessed for histopathology; therefore, it was undetermined whether bile duct-pancreatic fluid flow was occurring because of pancreatic damage. Liver damage was ruled out because benzene is not hepatotoxic.

It should be noted that IDDM is associated with a variety of hematologic changes (such as anemia) and malignancies (such as lymphocytic leukemia, lymphoma, and multiple myeloma) that might be directly related to or simply coincidental with the diabetes (430). From the literature reported in the sections on anemia and cancer, it can be seen that all of these conditions are also associated with exposure to benzene.

According to Bennett (431), corticosteroids are associated with the development of diabetes by reducing insulin sensitivity, or possibly by impairing islet function frequently associated with the development of impaired glucose tolerance. The secretion of anti-insulin hormones, such as growth hormones or adrenocorticotrophic hormone (ACTH), are also believed to play an important role in IDDM development (432). Steroid hormones play an important role in determining the severity of beta cell damage in the infected mouse, with androgens and glucocorticoids being particularly critical (433). For example, diabetes fails to develop in infected castrated males unless androgens are administered. In mice treated with corticosteroids, coagulative necrosis of the islets of Langerhans develops accompanied by severe hyperglycemia (433). Benzene has been shown to stimulate the hypothalamic-pituitary-adrenocortical (HPA) axis of mice (434), accompanied by increased ACTH/corticosterone release into blood. The HPA axis is responsible for releasing biogenic amines from the hypothalamus, ACTH from the pituitary, and corticosteroids from the adrenal cortex (435,436).

It has been demonstrated that most IDDM patients have autoantibodies to the pancreas (437), as well as to other organs (420,421,438-441). Autoantibodies have also been reported in animals chronically exposed to small doses of benzene (442). Additionally, benzene is known to affect the immune system in other ways (49,79,80,99,149,189,231,443-445) which might have an impact on the development of diabetes. In conclusion, although the literature suggests an association between benzene exposure and the development of IDDM, such a determination is premature.

Kidney Disease

Kidney disease was reported in excess for males and females in the 55 through 64 years of age group at Baseline; no other excesses were found for this outcome. The Subregistry and NHIS questions for this outcome were a close match.

No studies were located that specifically addressed the potential for development of noncarcinogenic kidney disease following exposure to benzene; however, reports of miscellaneous cases of kidney outcomes-Goodpasture syndrome (glomerulonephritis) and antiglomerular basement membrane antibody (446), nephrotoxic anuria (447), and kidney congestion (411)-were found. Both rats (448) and mice (449) orally exposed to benzene at varying levels did not develop any adverse kidney conditions.

Liver Problems

The overall rates of liver problems for the Benzene Subregistry population were statistically significantly higher than those for the NHIS population at Followups 1 and 2. The Subregistry and NHIS questions for this outcome were a close match.

No studies were located that addressed the effect of benzene on the human liver. Several animal studies, however, were identified. Constan et al. (450) evaluated apoptosis in the livers of Fischer-344 rats following exposure to drinking water containing seven contaminants, one of which was benzene. The authors deduced that apoptosis was directly correlated with changes in cell proliferation that were produced by repeated exposures to the contaminants. Ugurnal et al. (451) investigated the effect of acute and chronic benzene treatment on the lipid peroxidation and antioxidant system in mouse liver. Malondialdehyde and diene conjugate levels were found to be increased in liver homogenates and microsomes of chronically exposed mice and were unchanged in the acutely exposed; glutathione levels remained unchanged in liver homogenates of all treatment groups. Some parameters, including cytosolic total glutathione peroxidase and glutathione transferase, were increased, but others (selenium-dependent glutathione peroxidase and superoxide dismutase) remained unchanged.

Pawar and Mungikar (452) investigated the effect of administering 1,400 mg/kg/day benzene to rats. They found an increase in liver weight in the exposed animals, as well as a decrease in protein in the postmitochondrial supernatant fractions. They also identified changes in hepatic drug metabolism and lipid peroxidation in the exposed animals.

Negative studies were also located. Tatrai et al. (239) found slight increases in relative liver weight of CFY rats exposed to 125 ppm benzene for 24 hours per day during gestational days 7 through 13; this outcome was not considered to be adverse, however. No adverse hepatic effects were observed in B6C3F1 mice exposed to 0, 12, 195, or 350 mg/kg benzene in drinking water for 30 days (449).

Neurotoxicity (Hearing and Speech Impairments and Mental Retardation)

The potential for benzene to have neurotoxic effects was assessed by the Benzene Subregistry through the assessment of three health outcomes-hearing impairments, mental retardation, and speech impairments. The questions on the NHIS and Benzene Subregistry questionnaires for mental retardation were the same, for hearing impairments were a close match, and for speech impairments were similar, but not close matches. There were no differences in rates between the Benzene Subregistry and NHIS for mental retardation for all time frames. Hearing impairments were significantly lower overall at all reporting periods, for males 31 through 50 years of age, and for females 31 through 40 years of age at Followup 4.in the Benzene Subregistry population. Speech impairments were statistically significantly overall for registrants at Followup 1; otherwise reporting rates were the same as for NHIS.

Benzene at high levels has been shown to affect both the peripheral (453) and central (64,110,454) nervous systems. The signs and symptoms reported include vertigo, drowsiness, euphoria, headache, giddiness, narcosis, muscular incoordination, convulsions, paralysis, and unconsciousness (149,410,454-456). Chronic industrial exposure has also been reported to cause neurological abnormalities, such as global atrophy of the lower extremities and distal neuropathy of the upper extremities (457), as well as abnormal electroencephalograms (458,459).

Most exposures to benzene occur in the workplace over a relatively short period of time. For example, Midzenski et al. (92) reported on 15 degassers who were acutely exposed to >60 ppm benzene over several days. Medical surveillance evaluation initially revealed 11 workers (73%) with neurotoxic symptoms. In addition, workers with more than 16 hours of acute exposure were significantly more likely to report dizziness and nausea than those with less than 16 hours of acute exposure. According to Fielder and coworkers (410), fatalities have also been reported due to the inhalation of high concentrations of benzene in occupational settings, primarily in enclosed spaces such as tanks containing high residual levels of benzene. The findings at autopsy in these cases included extensive petechial hemorrhages in the brain. The authors estimated that inhalation exposure to 20,000 ppm benzene is likely to be rapidly fatal, 7,500 ppm is dangerous after 30 to 60 minutes, and 3,000 ppm is tolerable for only about 30 minutes.

Only one study was located that could possibly link the health outcomes of speech impairment, hearing impairment, or mental retardation with benzene exposure. Akefeldt et al. (460) investigated whether parental age and parental preconceptional exposure to various agents, including gasoline or petrol (of which benzene is a major constituent) differentiated children with Prader-Willi syndrome (PWS) from obese children without PWS. (Note: PWS is a congenital disorder characterized by rounded face, almond-shaped eyes, strabismus, low forehead, hypogonadism, hypotonia, insatiable appetite, and mental retardation). They found that paternal exposure to gasoline or petrol was significantly higher in the PWS group.

In animals, only one animal study was located that discussed the potential for hearing damage following benzene exposure. Tilson and coworkers (461) reported that preweaning exposure to benzene had no significant effect on the acoustic startle response in rats. Other studies, however, have indicated that benzene is indeed a neurotoxicant. Acute exposures to high concentrations (>10,000 ppm) of benzene have been shown to be fatal to animals because of the direct narcotic effects (455,462,463); the threshold for narcotic effects has been estimated to be about 4,000 ppm (64,410).

Other neurological effects have also been reported. Dempster et al. (464) reported a 90% decrease in the hind limb grip strength of C57BL/6 mice following a single exposure to 1,000 or 3,000 ppm benzene. Animals in the 3,000-ppm group also had tremors that disappeared after exposure ceased. Evans et al. (465) reported increased behavioral activity in male CD-1 and C57BL/6 mice 2 weeks after exposure to 300 or 900 ppm benzene for 6 hours per day for 5 days. Narcosis was reported in mice in the 900-ppm group. Piloerection, excitation, and tremors were reported for C57BL/6 mice exposed to 440 to 660 mg/kg benzene (466).

Hsieh and coworkers (189,434) have investigated the effect of benzene exposure on the brain of CD-1 mice, specifically on the catecholamines norepinephrine and dopamine; the catecholamine metabolites vanillylmandelic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid; and the indoleamine serotonin and its metabolite 5-hydroxy-indoleacetic acid. They found that benzene produced increases of norepinephrine in the hypothalamus, cortex, midbrain, and medulla oblongata; dopamine in the hypothalamus and corpus striatum; and serotonin in all dissected brain regions except the cerebellum. They also reported elevated levels of various monoamine metabolites in these areas. These neurochemicals are known to play important roles in behavior (467,468). Finally, these authors found that benzene stimulated HPA activity, which is critically involved in the regulation of behavioral adaptations (435,436). Li et al. (186) reported increased levels of acetylcholinesterase in the brains of mice exposed to 3 ppm benzene for 2 hours each day for 30 days. Finally, in another study, de Gandarias et al. (469) investigated the changes in Lys- and Leu-aminopeptidase activities in several rat brain regions after benzene administration. They found that the activity of both enzymes were significantly decreased in the thalamus, hypothalamus, hippocampus, and amygdala.

Only one study was located that reported negative results. McMurry et al. (444) found no gross behavioral changes in cotton rats exposed to benzene.

Respiratory Conditions (Asthma, Emphysema, and Chronic Bronchitis and Respiratory Allergies or Problems, Such as Hay Fever)

There were no statistically significantly increased reports of asthma, emphysema, and chronic bronchitis for registrants for any time period; however, registrants reported statistically significantly lower rates overall at Baseline and for females 11 through 18 years of age at Followup 1. Registrants reporting rates for respiratory allergies or problems such as hay fever were statistically significantly higher than those for NHIS as follows: at Baseline for those 0 through 9 years of age; at Followup 1 for males and females 1 through 10 years of age and females 56 through 65 years of age; at Followup 2 for males and females 2 through 11 years of age; at Followup 3 for those 4 through 13 and those 39 through 48 years of age; and at Followup 4 overall and for males 6 through 15, 41 through 50, and 51 through 60 years of age and for females 6 through 15 and 31 through 40 years of age. The Subregistry and NHIS questions for asthma, emphysema, and chronic bronchitis were the same and the questions for respiratory allergies or problems, such as hay fever were close matches.

According to the National Institute for Occupational Safety and Health (NIOSH) (249), acute exposure to relatively high levels of benzene in air has been reported to cause respiratory irritation, pulmonary edema, and pneumonia. Chronic exposure to benzene in air can cause labored breathing. In a case report of three fatalities due to acute benzene exposure aboard a chemical cargo ship, Avis and Hutton (409) reported evidence existed of respiratory injury, including hemorrhagic airless lungs with confluent alveolar hemorrhage, and pulmonary edema. Other studies have reported petechial hemorrhages in the pleura (410), respiratory tract inflammation and lung hemorrhages (411), irritation of the respiratory tract (456), and intra-alveolar pulmonary (446). Workers exposed to >60 ppm benzene for up to 3 weeks reported mucous membrane irritation and dyspnea (92).

In a mortality study of refinery workers in California, Wong (160,319) reported substantially lower death rates from nonmalignant diseases of the respiratory system. This finding was confirmed in a followup of the cohort by Dagg and coworkers (161). In a similar study, Zoloth et al. (131) reported a significantly reduced death rate from emphysema in commercial pressmen.

In animals, acute inhalation of benzene by rats, mice, and rabbits caused respiratory paralysis. Also in animals, the lungs, spleen, and lymphatic system showed signs of damage that became more pronounced after exposure to both benzene and ethanol (470). Deichman et al. (191) reported that the most consistent and significant pathological change in Sprague-Dawley rats exposed to benzene was chronic bronchopneumonia. Driscoll and Snyder (471) reported that benzene exposure did not affect the respiratory rate or minute volume of mice; however, Sabourin et al. (51) found a significant decrease in the respiratory rate of mice (but not rats) treated with benzene. Finally, in a study of the ability of the lung to bioactivate or detoxify benzene and the pneumotoxicity of benzene, Chaney and Carlson (56) found that, although overall metabolism was lower, pulmonary microsomes converted benzene to hydroquinone; however, benzene, injected at a dose of 600 mg/kg body weight in rats, did not cause significant lung cell damage as determined by measurement of gamma-glutamyltransferase and lactate dehydrogenase in bronchoalveolar lavage fluid. Given the types of studies reported in the literature and the information available for the registrants, no obvious conclusions could be reached regarding the association between benzene and this health condition.

Skin Rashes, Eczema, or Other Skin Allergies

There was statistically significantly increased reporting of skin rashes for registrants 0 through 9 years of age at Baseline, those 1 through 10 years of age at Followup 1, overall at Followup 3, and overall and for males 61 through 70 years of age at Followup 4. There were no differences in reporting rates between the Benzene Subregistry and NHIS at Followup 2. The corresponding questions for this outcome on the Benzene Subregistry and NHIS questionnaires were similar but not close matches.

In humans, most dermal exposures to benzene have occurred in the occupational setting. Occupational exposures to benzene at levels >60 ppm in air for up to 3 weeks resulted in skin irritation (92). Other effects seen in other case reports include dry, scaly dermatitis (410); marked irritation due to the defatting action of the solvent (455,472); swelling and edema (473); and erythema and vesiculation (474)and genitoanocrural porokeratosis (475). In fatal cases, extensive petechial hemorrhages (410) and second-degree chemical burns to the face, trunk, and limbs (409) were reported.

Few animal studies were located in which the dermal effects of benzene were studied. When applied to the skin of rabbits, benzene caused moderate erythema and edema, and moderate necrosis (164). In guinea pigs, benzene caused significant skin changes, and possible irreversible cellular injury, within 15 minutes of topical application (476). Decreased skin collagen content (236), edema (477), and alopecia (448) have also been reported for animals exposed to benzene by various routes. Skin cancers, including cutaneous papillomas and squamous cell carcinomas (28) have been reported in rats.

As can be seen, the literature is too sparse to attempt to draw conclusions about the potential for exposure to benzene in the environment to result in disorders of the skin.

Ulcers, Gallbladder Trouble, or Stomach or Intestinal Problems

Increased rates of stomach problems related to ulcers, gallbladder trouble, and stomach or intestinal problems were reported for female registrants 1 through 10 years of age at Followup 1 and females registrants 4 through 13 years of age at Followup 3. The NHIS and Subregistry questions for this outcome were similar, but not close matches.

According to the literature, short-term (acute) exposure to benzene in the occupational setting has caused nausea and gastrointestinal irritation (249); however, the doses were relatively large. Chronic exposure to benzene in the workplace has been reported to produce anorexia (249). One case report was located in which a man swallowed an unspecified amount of benzene and survived, but developed an intense toxic gastritis and later pyloric stenosis (30). According to Drozd and Bockowski (456), early symptoms of benzene toxicity include nausea and vomiting. For these conditions, however, there appears to be no association between reported rates in the literature and the reporting rates of the registrants.

Urinary Tract Disorders, Including Prostate Trouble

In interpreting the results for urinary tract disorders, including prostate trouble, the wording of the questions for the NHIS and Subregistry questionnaires differs and might have been a factor in the results obtained (urinary tract disorders, including prostate trouble, were included in the Subregistry questionnaire; disorders of the bladder, other than bladder infections, and diseases of the prostate were included in the NHIS questionnaire). Registrants reported higher rates of urinary tract problems than NHIS participants as follows: for all females and females 0 through 17 and 25 through 44 years of age at Baseline; overall for females 1 through 45 years of age and for males 1 through 10 and 26 through 45 years of age at Followup 1; overall, for females 2 through 11 and 20 through 46 years of age, and for males 37 through 46 years of age at Followup 2; for all females at Followup 3; and for all females and females 16 through 50 years of age at Followup 4.

Wong (319) investigated mortality in refinery workers in California and found significantly lower rates for diseases of the genitourinary system for benzene-exposed workers. A followup of this cohort (161) confirmed these findings; however, women were excluded from most of the analyses because of low numbers. In addition, the authors noted a strong "healthy worker" effect in this population. It should be noted that no studies were located specifically addressing the potential effects of benzene exposure on the development of prostate disorders.

Urinary tract disorders are frequently related to infection. Although not assessed directly through the Benzene Subregistry, immune system effects do play a role in several of the outcomes that were assessed, such as infections for kidney disease and urinary tract problems and autoimmune components of diabetes and anemia. It is therefore important to review reported effects on the immune system following benzene exposure.

Benzene is a known immunotoxicant (31,444,478). As discussed in the section on anemia, benzene does cause changes in circulating leukocytes, including lymphocytes (30,123,140,142,479,480); in addition, benzene-induced aplastic anemia has peripheral lymphocytopenia as an early distinctive feature of the disease (34,108,481,482). It should be noted that there are indications that benzene has a greater depressive effect on T lymphocytes than on B cells (348). Zeman et al. (443) reported decreased CD4:CD8 lymphocyte ratios, abnormal values for lymphocyte populations, and impaired lymphocyte function in petroleum workers exposed to up to 20 milligrams per cubic meter (mg/m3) benzene for 5 years. Changes in humoral immunity have been reported for workers exposed to, but not seriously intoxicated by, benzene (483,484); IgA and IgG levels were reduced, but IgM levels were slightly higher. There were, however, concomitant exposures to other solvents. Finally, a reduced mitogenic response of lymphocytes was reported for a population occupationally exposed to low levels of benzene (485).

Benzene also affects both humoral and cellular acquired immunity in animals (28,30,99,164,166-169,171,184,200,486). As early as 1915 (487), studies of rabbits exposed to benzene revealed reduced production of red cell lysins, of agglutinins for killed typhoid bacilli, and of opsonins and the absence of antibacterial antibodies (488,489). Benzene is highly toxic to bone marrow stem cells (490), as well as mitotic cells and lymphocytes, especially B cells and suppressor T cells (31,184). Benzene metabolites have also been shown to exert adverse effects on human lymphocytes in vitro (491).

Several studies implicate the immune system as a target for benzene. Inhalation or injection of benzene has been shown to suppress the mitogenic response of B and T lymphocytes (99,200,466,486). Other immune system effects seen in animals include development of lymphopenia (99), involution of thymic mass, suppression of mixed lymphocyte culture response to alloantigens, suppression of the tumor lytic ability of cytotoxic T lymphocytes as determined by 51Cr-release assay, and production of antibodies in response to T-dependent antigen (sheep red blood cells) (99,184,230,466,486). IgM levels were also reported to be reduced in benzene-exposed mice (466). Animal studies have further defined the effects of benzene exposure on the immune system. Female C57BL/6 mice dosed with benzene at 220, 440, or 880 mg/kg/day for 14 days demonstrated significant decreases in splenocyte proliferation (445). A decrease in spleen weight and in the number of circulating leukocytes have been reported in numerous other animal studies (28,49,164,167-169,185,186,188,480,492,493). For example, Farris et al. (494) reported that exposure to 100 or 200 ppm benzene induced rapid and persistent reductions in femoral B-, splenic T- and B-, and thymic T-lymphocytes. Inhibition of interleukin-2 (IL-2) production has been demonstrated following exposure to benzene (99,206,434,445,492). One interesting note is the report of the production of autoantibodies in animals chronically exposed to small doses of benzene (442,495). Ethanol can enhance the immunosuppressive effects of benzene (231,470).

Benzene also affects functional immunity (49,177,496). Indeed, as early as 1913, studies indicated that benzene-exposed rabbits displayed an increased susceptibility to pneumonia (497,498) and tuberculosis (499). Later studies have also indicated decreased responses to pathogenic microorganisms, such as Listeria monocytogenes (500) and Klebsiella pneumoniae (501). Concentrations of 200 or 400 ppm for 4 to 5 weeks (5 days per week) suppressed the primary antibody response to tetanus toxin in mice, but there was no effect at 50 ppm (30).

The metabolites of benzene have also been shown to affect the immune system of animals. These effects include inhibition of IL-2 production (206); inhibition of maturation and proliferation of B lymphocyte progenitors (206,230); depression of numbers of B and T lymphocytes in the marrow, spleen, and thymus (206,225,227-229); inhibited macrophage activity (207); interference with microtubule assembly (227,502); decreased bone marrow cellularity (230); inhibition of pre-B cells (IgM-) from maturing to IgM+ cells, as well as reduction of the ability of mitogens to stimulate the proliferation of IgM+ cells to CFU-B colonies (503). It should be noted that benzene and benzene metabolites are not always suppressive (79,444) and at low doses (228) or on cell-mediated immunity (184) can be stimulatory.

Inhibition of proliferation and production of the T cell lymphokine IL-2 has been seen in mice exposed to p-benzoquinone (206) as well as to benzene (189). As discussed in the section on diabetes, benzene can also have an adverse effect on immune function by means of an activated HPA system (434), which is responsible for the production of corticosteroids from the adrenal cortex (435,436). Corticosteroids have been reported to inhibit both interleukin-1 (IL-1) and IL-2 production (504-506). Benzene can also have a pronounced effect on other brain neurotransmitters (507-509). In addition, it has recently been demonstrated that various benzene metabolites depress the production of interferon (348,510). Acute benzene exposure induced neither immunosuppression nor stimulation in cotton rats (444), results that were believed to be caused by species variation.

According to Kalf (231), the immunosuppressive effects of benzene can be altered by other substances. For example, prior administration of a product from Aspergillus ochraceous, which has interferon-inducing properties, has been reported to modulate the effects of benzene exposure (511). Ingestion of ethanol also increases immunosupression by benzene (88), as well as benzene-induced hematotoxicity (94) in experimental animals.

There were only a few reported cancers of the urinary organs in the time frames "ever had" or "within the last 12 months" for the Benzene Subregistry. Wong (160) reported the SMR (140.0) for kidney cancer for continuously exposed workers to be three times that for the occupationally unexposed (48.4). In addition, a study of workers having potential exposure to downstream gasoline at oil distribution centers in the United Kingdom found a significant excess of kidney and suprarenal cancer (512). Negative reports of risk of developing renal cancer following benzene exposure were also found. Enterline and Viren (327) reviewed the epidemiologic evidence for an association between petrol (gasoline) exposure and kidney cancer and concluded that there was little support for an etiologic link in the 12 cohort, 3 case referent, and 3 ecologic studies included in their review. Similar conclusions had been reached in a workshop on the subject a year earlier (328) and in a 1987 review of several cohort studies examining the relationship between organic solvents and renal cancer (330). Three additional studies (331-333) also found no relationship between exposure to solvents and renal cancer.

Although the literature is too sparse to draw conclusions about any associations between benzene exposure and the development of kidney disease, the literature definitely supports an association between benzene exposure and adverse effects on functional immunity. Further investigation of the causes of the reported cases of kidney disease in the Benzene Subregistry would assist researchers in determining whether immune system dysfunction played a role in the development of kidney disease in this population.

SUMMARY

This section has reviewed the most current scientific literature for benzene exposure and health effects. The literature suggests that there might be associations between benzene exposure and some of the health outcomes that have been reported as excess by the Subregistry data. However, the reported literature has many limitations-case reports of occupational studies usually involve only males; exposure levels in occupational exposures are much higher than those reported in environmental exposures; and high-dose animal studies may not be relevant to humans. In addition, human health studies often lack sufficient exposure characterization, lack controls for important confounding factors, and do not include sample sizes large enough to investigate low-dose effects. These and other limitations must be considered by the reader. This section does not support a cause-and-effect relationship between benzene exposure and human health outcomes among the Benzene Subregistry population.

SECTION 11: CONCLUSIONS AND RECOMMENDATIONS

CONCLUSIONS

The Benzene Subregistry is a database containing self-reported health information for 1,143 persons (1,127 living and 16 deceased) who had been exposed to benzene through the drinking water used in their homes. Using the available environmental data, probable start dates for exposure were established; the end dates were known. The registrants of Three Lakes Municipal Utilities District (TLMUD), Texas, had been potentially exposed to a maximum level of 66.0 ppb for up to 12 years. Dose calculations will be considered in the future for the Benzene Subregistry population. Recently, several computer models (513-515) have become available with which exposure patterns can be simulated with a minimum amount of information. Perhaps these models could be used in conjunction with statistical models to develop a best estimate of actual environmental levels for all exposure periods and sites. If this is feasible, individual doses might be reconstructed for all routes of exposure for further use in dose-response evaluations.

Cause-and-effect relationships between benzene exposure and reported health outcomes cannot be established using the Benzene Subregistry data; however, potential associations can be identified. There are biases and limitations of the Subregistry data files that should be considered in assessing the validity of the suggested associations. A bias in reporting may occur because of the registrants' awareness of their exposure and possible resulting actions-for example, seeking medical care more often. To moderate this possible reporting bias, the qualifier that a health care provider must have told the registrant about or treated the registrant for the reported health outcome was required (the qualifier was not required of the comparison population). The wording for the health questions (potentially two) of the NER and the NHIS data collection instruments is different. And finally, although the significant level for the statistical analyses is low (α = 0.01) and the sample size is large, given the large number of comparisons made, there is a potential for false positives.

The Benzene Subregistry population reported positively more often for some health outcomes, less often for others, than the national norms (NHIS). Statistically significantly increased reporting was found for Benzene Subregistry members at various interview periods, in most cases for select age and sex groups for the health conditions anemia and other blood disorders; arthritis, rheumatism, and other joint disorders; cancer; diabetes; skin rashes, eczema, and other skin allergies; effects of stroke; ulcers, gallbladder trouble and other stomach and intestinal problems; and urinary tract disorders, including prostate trouble.

Statistically significantly decreased reporting by the Benzene Subregistry members was found for the conditions hearing and speech impairments, asthma and emphysema, and arthritis. This confirmed expectations, given that some of these are often self-diagnosed health conditions and would, therefore, be most affected by the limitations of health care provider confirmation of the existence of a given condition.

RECOMMENDATIONS

Information obtained from this database can and will be used to suggest possible benzene exposure-health outcome associations and to determine appropriate future activities and research. Considerations for further research using this database include:

* New methods will be explored to characterize the environmental exposures of registrants. Dose-response relationships will be further explored by means of strategies currently being investigated by ATSDR.

* Additional information is needed about the people in the Benzene Subregistry population who reported health outcomes identified as excess. The types of information that might prove useful include further details of health conditions from medical files, information on lifestyle factors (such as alcohol consumption or diet), or information on occupational exposures that might relate to another potentially causative factor. In the future, ATSDR will contact appropriate registrants to obtain their permission to access this information. These data, along with data obtained from continued followup of the registrants and confirmation of medical conditions, will aid in further exploration of possible linkages.

* Wording differences between Benzene Subregistry questions will be evaluated and modified so that they are more closely aligned with the appropriate NHIS questions.

* The data file, without personal identifiers, will be made available to the public via the Internet. Other researchers are encouraged to study these reported results more extensively and to undertake other analyses.

* For eligible people who are deceased, death certificates will be obtained and pertinent information abstracted. A mortality file will be constructed and comparisons will be made using the appropriate national norms.

Preliminary findings from the completed analyses leave many questions unanswered; it is hoped that additional information and further investigations will help answer these questions. Routine longitudinal followup of the Benzene Subregistry population will continue. The additional information collected will be used to assess trends in reporting and to assist in answering or clarifying some of the issues and questions previously discussed.

It should be noted that all of the health conditions that were reported in excess by the Benzene Subregistry population are preventable or treatable, if not curable. Early detection frequently plays a role in whether a health condition can be arrested or reversed by existing medical technologies. Given the results of the baseline analyses for this population, it was imperative that this information be shared with the Benzene Subregistry population in a responsible manner.

A summary version of the Benzene Subregistry Baseline Through Followup 4 Technical Report, the Benzene Registrant Report, as well as a one-page fact sheet, were composed in nontechnical language for release to the registrants. A Subregistry Technical Assistance Panel (STAP), which was composed of representative membership from the states involved, other federal agencies, and other knowledgeable persons, reviewed the findings from these reports and gave ATSDR suggestions and recommendations about future activities that would be appropriate for followup to release of the information.

Following review by the STAP, information packets containing the registrant report, fact sheet, and cover letter were mailed to all Benzene Subregistry members. Similar information was mailed to the media shortly after the registrants receive their information packets. A public availability meeting was held in the Three Lakes Municipal Utilities District. The public meeting was conducted to review the purpose of the Benzene Subregistry and the information provided to the registrants. Registrants were encouraged to ask questions of ATSDR, either in person or by telephone.

Those registrants expressing specific health concerns were encouraged to see their personal physicians. A concerted effort was made by ATSDR to share the findings of the Benzene Subregistry analyses with the appropriate health care providers in each area. In addition, specific information about benzene and training about health effects associated with benzene exposure was made available to them.

Although no definitive conclusions can be drawn from the information contained in this report, it is hoped that researchers will use the information to better assess the potential for adverse health outcomes following exposure to chemicals in the environment. As has been pointed out, additional studies of the Benzene Subregistry data are warranted and encouraged by ATSDR.

AUTHORS AND ACKNOWLEDGEMENTS

Authors
Ginger L. Gist, PhD[1]
Carla F. Boudreau, M.S.[1]
L. Laszlo Pallos, Ph.D.[1]
Acknowledgments

The authors wish to acknowledge the assistance provided by Caroline D. Cusack, Glenda Sentelle, Jay Sapp, Tim Copeland, and Terica Boyer, Exposure and Disease Registry Branch, Division of Health Studies; Jeffrey Lybarger, Sharon Campolucci, and Nancy Whitehead, Office of the Director, Division of Health Studies; Henry Falk and Robert Spengler, Office of the Assistant Administrator, Agency for Toxic Substances and Disease Registry. The authors also wish to thank Anthony Bennett, Texas Natural Resources and Conservation Commission; Dr. John Vilanacci and Judy Henry, Texas Department of Health; and John Williams, Harris County Health Department.

The authors wish to thank the following people who served as technical reviewers and contributed a great deal:

The Benzene Subregistry would never have been possible without the efforts of Dr. JeAnne R. Burg. The authors are grateful for her years of effort on behalf of the National Exposure Registry.

Above all, the authors wish to thank the Benzene Subregistry members for their participation in this endeavor.

Affiliations

[1]Exposure and Disease Registry Branch, Division of Health Studies, Agency for Toxic Substances and Disease Registry, Atlanta, Georgia.

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U.S. Department Of Health And Human Services Public Health Service Agency For Toxic Substances And Disease Registry

National Exposure Registry Benzene Subregistry Baseline Through Followup 4 Technical Report February 2001

DISCLAIMER

CONTENTS

EXECUTIVE SUMMARY

SECTION 1: INTRODUCTION

SECTION 2: BACKGROUND OF THE BENZENE SUBREGISTRY

SELECTION OF BENZENE AS A PRIMARY CONTAMINANT

SELECTION AND DESCRIPTION OF BENZENE SITE

DATA COLLECTION

SECTION 3: METHODS FOR DATA ANALYSES

RATIONALE FOR THE COMPARISON OF THE BENZENE SUBREGISTRY DATA WITH NATIONAL DATA

METHODS OF DESCRIPTIVE VARIABLE COMPARISONS

Demographic Characteristics

Cigarette Smoking

METHODS OF COMPARING HEALTH OUTCOMES

Question Comparability

Calculation of NHIS Rates

Statistical Analysis of Health Data

Statistical Analysis of Cancer Data

SECTION 4: RESULTS OF DESCRIPTIVE COMPARISONS

REGISTRANT DESCRIPTIVE DATA

Demographic Characteristics

Cigarette Smoking

SECTION 5: RESULTS OF HEALTH OUTCOME COMPARISONS

Anemia or Other Blood Disorders

Arthritis, Rheumatism, or Other Joint Disorders

Asthma, Emphysema, or Chronic Bronchitis

Cancers

Diabetes

Hearing Impairment

High Blood Pressure (Hypertension)

Kidney Disease

Liver Problems

Mental Retardation

Skin Rashes, Eczema, or Other Skin Allergies

Speech Impairment

Effects of Stroke

Ulcers, Gallbladder Trouble, and Stomach or Intestinal Problems

Urinary Tract Disorders, Including Prostate Trouble

SUMMARY

SECTION 6: RESULTS OF HEALTH OUTCOME COMPARISONS-FOLLOWUP 1

CONTROLLING FOR AGE AND SEX

Asthma, Emphysema, or Chronic Bronchitis

Cancers

Diabetes

Hearing Impairment

High Blood Pressure (Hypertension)

Kidney Disease

Liver Problems

Mental Retardation

Other Respiratory Allergies or Problems, Such as Hay Fever

Skin Rashes, Eczema, or Other Skin Allergies

Speech Impairment

Ulcers, Gallbladder Trouble, and Stomach or Intestinal Problems

Urinary Tract Disorders, Including Prostate Trouble

SUMMARY

SECTION 7: RESULTS OF HEALTH OUTCOME COMPARISONS-FOLLOWUP 2

CONTROLLING FOR AGE AND SEX

Arthritis, Rheumatism, or Other Joint Disorders

Asthma, Emphysema, or Chronic Bronchitis

Cancers

Diabetes

Hypertension

Kidney Disease

Liver Problems

Mental Retardation

Skin Rashes, Eczema, or Other Skin Allergies

Speech Impairment

Effects of Stroke

Ulcers, Gallbladder Trouble, and Stomach or Intestinal Problems

Urinary Tract Disorders, Including Prostate Trouble

SUMMARY

SECTION 8: RESULTS OF HEALTH OUTCOME COMPARISONS-FOLLOWUP 3

CONTROLLING FOR AGE AND SEX

Anemia or Other Blood Disorders

Arthritis, Rheumatism, or Other Joint Disorders

Asthma, Emphysema, or Chronic Bronchitis

Cancers

Diabetes