From: Rich Murray [rmforall@att.net] Sent: Monday, August 05, 2002 5:38 AM To: fdadockets@oc.fda.gov Subject: RTM: FDA: (Section E) 18 recent formaldehyde toxicity [Comet assay] abstracts 6.25.1 rmforall RTM: FDA: (Section E) 18 recent formaldehyde toxicity [Comet assay] abstracts 6.25.1 rmforall http://groups.yahoo.com/group/aspartameNM/message/645 [ See also, re formaldehyde neurotoxicity: http://groups.yahoo.com/group/aspartameNM/message/628 Rich Murray: Professional House Doctors: Singer: EPA: CPSC: formaldehyde toxicity 6.10.1 rmforall ] A millenium surge in formaldehyde toxicity research is noticable at: www.ncbi.nlm.nih.gov/PubMed . The new, fast, sensitive convenient Comet assay, which can reveal genetic damage in a single white blood cell, is being widely used to study the details of cellular damage from formaldehyde, one of the most potent, cumulative toxins, produced by the liver from methanol (wood alcohol), which in turn happens to be 10% of the sweetener aspartame, used by 200 million, sadly misled by the incessant industry refrain: "Aspartame is the most widely tested food additive in history." As a medical layman, I can safely mention that DNA-protein crosslinks means: cellular malfunctions and death, mutations, cancers, and birth defects. I hope some of these teams will immediately study the white blood cells of the many aspartame reactors, people who report a dismaying, bewildering suite of symptoms after months and years of 1-4 L/day use of diet drinks, which translates to 56 - 224 mg methanol. Results could be quickly and definitively achieved that would be of immense scientific and public health value. Can a medical doctor send a sample of his patient's blood to any of these labs for testing? What would be the procedure, and cost? Could medical insurance support innovative diagnostic research of the greatest value, for the patient and for the public? How much genetic damage arises from daily use of aspartame? Woodrow C. Monte, Director, Food Science and Nutrition Laboratory 602-965-6938 Arizona State University, woody.monte@asu.edu, "Aspartame: Methanol and the Public Health," 1984, J. Applied Nutrition, 36(1), 42-54 (62 references): The methanol from 2 L of diet soda, 5.6 12-oz cans, 20 mg/can, is 112 mg, 10% of the aspartame. The EPA limit for water is 7.8 mg daily for methanol (wood alcohol), a deadly cumulative poison. Many users drink 1-4 L daily. The reported symptoms are entirely consistent with chronic methanol toxicity. (Fresh orange juice has 34 mg/L, but, like all juices, has 16 times more ethanol, which strongly protects against methanol.) http://www.dorway.com/wmonte.txt Here is research in 1998 by C. Trocho et al, using a very low level of aspartame ingestion, 10 mg/kg, for rats, which have a much greater tolerance for aspartame than humans. So, the corresponding level for humans would be about 1 or 2 mg/kg. (Many headache studies in humans used doses of about 30 mg/kg daily.) This proves that aspartame causes binding of methanol's product, formaldehyde, a potent, cumulative toxin, into tissues. Life Sci June 26 1998; 63(5): 337-49 Full report: http://www.presidiotex.com/barcelona/index.html Formaldehyde derived from dietary aspartame binds to tissue components in vivo. Departament de Bioquimica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Spain. http://www.bq.ub.es/cindex.html Línies de Recerca: Toxicitat de l'aspartame http://www.bq.ub.es/grupno/grup-no.html Sra. Carme Trocho, Sra. Rosario Pardo, Dra. Immaculada Rafecas, Sr. Jordi Virgili, Dr. Xavier Remesar, Dr. Jose Antonio Fernandez-Lopez, Dr. Marià Alemany Fac. Biologia (male) Tel.: (93)4021521, FAX: (93)4021559 alemany@porthos.bio.ub.es bioq@sun.bq.ub.es josefer@porthos.bio.ub.es rafecas@porthos.bio.ub.es remesar@porthos.bio.ub.es Sra. Carme Trocho Fac. Biologia "Trok-ho" Tel.: (93)4021544, FAX: (93)4021559 Abstract: Adult male rats were given an oral dose of 10 mg/kg aspartame, 14C-labeled in the methanol carbon. At timed intervals of up to 6 hours, the radioactivity in plasma and several organs was investigated. Most of the radioactivity found (>98% in plasma, >75% in liver) was bound to protein. Label present in liver, plasma and kidney was in the range of 1-2% of total radioactivity administered per g or mL, changing little with time. Other organs (brown and white adipose tissues, muscle, brain, cornea and retina) contained levels of label in the range of 1/12th to 1/10th of that of liver. In all ,the rats retained, 6 hours after administration, about 5% of the label, half of it in the liver. The specific radioactivity of tissue protein, RNA and DNA was quite uniform. The protein label was concentrated in amino acids, different from methionine, and largely coincident with the result of protein exposure to labeled formaldehyde. DNA radioactivity was essentially in a single different adduct base, different from the normal bases present in DNA. The nature of the tissue label accumulated was, thus, a direct consequence of formaldehyde binding to tissue structures. The administration of labeled aspartame to a group of cirrhotic rats resulted in comparable label retention by tissue components, which suggests that liver function (or its defect) has little effect on formaldehyde formation from aspartame and binding to biological components. The chronic treatment of a series of rats with 200 mg/kg of non-labeled aspartame during 10 days results in the accumulation of even more label when given the radioactive bolus, suggesting that the amount of formaldehyde adducts coming from aspartame in tissue proteins and nucleic acids may be cumulative. It is concluded that aspartame consumption may constitute a hazard because of its contribution to the formation of formaldehyde adducts. PMID: 9714421, UI: 98378223 ******************************************************** Life Sci 1999;65(13):PL157-60 Comments on the purported generation of formaldehyde and adduct formation from the sweetener aspartame. Tephly TR Thomas R. Tephly 319-335-7979 thomas-tephly@uiowa.edu ttephly@blue.weeg.uiowa.edu Department of Pharmacology The University of Iowa, Iowa City 52242, USA. A recent paper by Trocho et al. (1) describes experiments meant to show that formaldehyde adducts are formed when rats are administered the sweetener aspartame. These authors assume that the methanol carbon of aspartame generates formaldehyde which then forms adducts with protein, DNA, and RNA. Doses employed range widely. In this letter, studies which have been published previously and which were not cited by these authors are reviewed in order to put into perspective the disposition of methanol and formaldehyde in monkeys and humans, species relevant to the toxicity of methanol and its toxic metabolite, formic acid. PMID: 10503962, UI: 99431287 A number of pro-aspartame studies by Tephly and associates, invariably funded by the aspartame industry (Monsanto, NutraSweet) are criticized in detail at: "Scientific Abuse in Aspartame Research" http://www.holisticmed.com/aspartame/abuse/methanol.html Aspartame Toxicity Information Center Mark D. Gold www.HolisticMed.com/aspartame 603-225-2100 mgold@tiac.net 12 East Side Drive #2-18 Concord, NH 03301 Carcinogenesis 1996 Jan;17(1):121-5 DNA--protein crosslinks, a biomarker of exposure to formaldehyde--in vitro and in vivo studies. Shaham J, Bomstein Y, Meltzer A, Kaufman Z, Palma E, Ribak J Occupational Cancer Unit, Occupational Health and Rehabilitation Institute, Loewenstein Hospital, P.O. Box 3, Ra'anana 43100, Israel. Judith Shaham, MD, is Instructor, Epidemiology and Preventive Medicine, Sackler Faculty of Medicine, Tel Aviv University. I could not find an email address for her, but an Associate Professor at her department is Beni Habot, MD, schmuelh@netfvision.net.il, whose work at the Geriatric Medical Center at Schmuel Harofe Hospital includes "poisoning of elderly", according to his website. Her coauthors are Yonit Bomstein, Alex Meltzer (or Melzer), and Joseph Ribak. Yonit Bomstein got his PhD in 1996 at Dept. of Immuniology, Feinberg Graduate School, Faculty of Biology, Weizmann Institute of Science, Rehovot, Israel, 972-8-934-2111 , 946-6966 fax, email rscien@weizmann.weizmann.ac.il , where he is a Research Student. Formaldehyde (FA) is a widely produced industrial chemical. Sufficient evidence exists to consider FA as an animal carcinogen. In humans the evidence is not conclusive. DNA-protein crosslinks (DPC) may be one of the early lesions in the carcinogenesis process in cells following exposures to carcinogens. It has been shown in in vitro tests that FA can form DPC. We examined the amount of DPC formation in human white blood cells exposed to FA in vitro and in white blood cells taken from 12 workers exposed to FA and eight controls. We found a significant difference (P = 0.03) in the amount of DPC among exposed (mean +/- SD 28 +/- 5%, minimum 21%, maximum 38%) than among the unexposed controls (mean +/- SD 22 +/- 6%, minimum 16%, maximum 32%). Of the 12 exposed workers, four (33%) showed crosslink values above the upper range of controls. We also found a linear relationship between years of exposure and the amount of DPC. We conclude that our data indicate a possible mechanism of FA carcinogenicity in humans and that DPC can be used as a method for biological monitoring of exposure to FA. PMID: 8565120, UI: 96152634 Int J Occup Environ Health 1997 Apr;3(2):95-104 DNA-Protein Crosslinks and Sister Chromatid Exchanges as Biomarkers of Exposure to Formaldehyde. Shaham J, Bomstein Y, Melzer A, Ribak J Occupational Cancer Unit, Occupational Health and Rehabilitation Institute, P.O. Box 3, Raanana 43100, Israel. [Record supplied by publisher] Formaldehyde is classified as a probable human carcinogen. DNA-protein crosslinks (DPCs) and sister chromatid exchanges (SCEs) may represent early lesions in the carcinogenic process. The authors examined the DPCs and SCEs in peripheral-blood lymphocytes of 12 and 13 workers exposed to formaldehyde and eight and 20 unexposed workers, respectively. The amounts of DPCs and SCEs in the exposed and the unexposed differed significantly after adjustment for smoking. There was a linear relationship between years of exposure and the amounts of DPC and SCE. The authors conclude that the data indicate a possible mechanism of carcinogenicity of formaldehyde, and that formaldehyde is mutagenic to humans. These results support the use of DPCs as a biomarker of occupational exposure to formaldehyde and to detect high-risk populations for secondary prevention. PMID: 9891106 Carcinogenesis 1996 Sep;17(9):2097-101 Comments on 'DNA-protein crosslinks, a biomarker of exposure to formaldehyde--in vitro and in vivo studies' by Shaham et al. Casanova M, Heck HD, Janszen D Publication Types: Letter PMID: 8824543, UI: 96421926 Mutat Res 2000 Sep 20;469(2):279-85 Evaluation of DNA damage in workers occupationally exposed to pesticides using single-cell gel electrophoresis (SCGE) assay. Pesticide genotoxicity revealed by comet assay. Garaj-Vrhovac V, Zeljezic D Mutagenesis Division, Institute for Medical Research and Occupational Health, Zagreb, Croatia. The comet assay, also called the single-cell gel electrophoresis (SCGE) assay, is a rapid and sensitive method for the detection of DNA damage (strand breaks and alkali-labile sites) in individual cells. The assay is based on the embedding of cells in agarose, their lysis in alkaline buffer and finally subjection to an electric current. In the present study, alkaline SCGE was used to evaluate the extent of primary DNA damage and DNA repair in peripheral blood lymphocytes of workers employed in pesticide production. After the period of high pesticide exposure, lymphocytes of the occupationally exposed workers manifested increased tail length and tail moment compared to the control group. After the workers spent 6 months out of the pesticide exposure zone, both endpoints were still above that of the control but significantly decreased as compared to the results of the first analysis. PMID: 10984689, UI: 20442322 Mutagenesis 2000 Jan;15(1):85-90 Induction and repair of formaldehyde-induced DNA-protein crosslinks in repair-deficient human cell lines. Speit G, Schutz P, Merk O Universitatsklinikum Ulm, Abteilung Medizinische Genetik, D-89070 Ulm, Germany. guenter.speit@medizin.uni-ulm.de We have previously shown that the alkaline Comet assay (single cell gel electrophoresis) in a modified version is a sensitive test for the detection of formaldehyde-induced DNA-protein crosslinks (DPC). Our results also indicated that formaldehyde-induced DPC are related to the formation of chromosomal effects such as micronuclei and sister chromatid exchanges. To better understand the genetic consequences of formaldehyde-induced DPC we have now investigated the induction and removal of DPC in relationship to the formation of micronuclei in normal and repair-deficient human cell lines. We did not find significant differences between normal cells, a xeroderma pigmentosum (XP) cell line and a Fanconi anaemia (FA) cell line with respect to the induction and removal of DPC. However, the induction of micronuclei was enhanced in both repair-deficient cell lines, particularly in XP cells, under the same treatment conditions. Comparative investigations with the DNA-DNA crosslinker mitomycin C (MMC) revealed a delayed removal of crosslinks and enhanced induction of micronuclei in both repair-deficient cell lines. FA cells were found to be particularly hypersensitive to micronucleus induction by MMC. In contrast to the results with formaldehyde, induction of micronuclei by MMC occurred at much lower concentrations than the effects in the Comet assay. Our results suggest that more than one repair pathway can be involved in the repair of crosslinks and that disturbed excision repair has more severe consequences with regard to the formation of chromosomal aberrations after formaldehyde treatment than has disturbed crosslink repair. PMID: 10640535, UI: 20109169 Teratog Carcinog Mutagen 2000;20(5):265-72 Chromosomal aberrations analysis in a brazilian population exposed to pesticides. Antonucci GA, de Syllos Colus IM Department of General Biology, CCB, State University of Londrina, PR, Brazil. In spite of being harmful, pesticides are widely used in Brazil. Their genotoxic effects might be studied through population monitoring by means of the analysis of chromosomal aberrations in occupationally exposed individuals. The aim of this study was to evaluate the chromosomal aberration frequencies in temporary cultures of lymphocytes from periferic blood of 23 workers professionally exposed to a mixture of pesticides. The workers were employed by the Agronomic Institute of Parana (Brazil) and used all of the prevention measures provided. A detailed history of pesticide use, as well as personal data, smoking habits, and history of recent illnesses and medical treatment were collected through a standardized questionnaire administered to each subject. Nonexposed subjects, matched for age, sex, and smoking habits, served as the negative control. A total of 100 cells were analyzed from each individual. A significant increase in chromosomal aberration frequencies was observed in exposed individuals when compared to the control group. Some individual characteristics such as age, sex, time of exposure to the pesticides, and smoking habits showed no correlation with chromosomal aberrations. Therefore, the positive results may be considered true effects of pesticides on human somatic cells. PMID: 10992273, UI: 20449336 Carcinogenesis 2000 Aug;21(8):1573-80 Loss of DNA-protein crosslinks from formaldehyde-exposed cells occurs through spontaneous hydrolysis and an active repair process linked to proteosome function. Quievryn, George A. ; Zhitkovich, Anatoly Department of Pathology and Laboratory Medicine, Brown University, Box G-B511, Providence, RI 02912, USA. George_Quievryn@brown.edu Anatoly_Zhitkovich@brown.edu DNA-protein crosslinks (DPC) involving all major histones are the dominant form of DNA damage in formaldehyde-exposed cells. In order to understand the repair mechanisms for these lesions we conducted detailed analysis of the stability of formaldehyde-induced DPC in vitro and in human cells. DNA-histone linkages were found to be hydrolytically unstable, with t(1/2) = 18.3 h at 37 degrees C. When histones were allowed to remain bound to DNA after crosslink breakage, the half-life of DPC increased to 26.3 h. This suggests that approximately 30% of spontaneously broken DPC could be re-established under physiological conditions. The half-lives of DPC in three human cell lines (HF/SV fibroblasts, kidney Ad293 and lung A549 cells) were similar and averaged 12.5 h (range 11.6-13.0 h). After adjustment for spontaneous loss, an active repair process was calculated to eliminate DPC from these cells with an average t(1/2) = 23.3 h. Removal of DPC from peripheral human lymphocytes was slower (t(1/2) = 18.1 h), due to inefficient active repair (t(1/2) = 66.6 h). This indicates that the major portion of DPC is lost from lymphocytes through spontaneous hydrolysis rather than being actively repaired. Depletion of intracellular glutathione from A549 cells had no significant effect on the initial levels of DPC, the rate of their repair or cell survival. Nucleotide excision repair does not appear to be involved in the removal of DPC, since the kinetics of DPC elimination in XP-A and XP-F fibroblasts were very similar to normal cells. Incubation of normal or XP-A cells with lactacystin, a specific inhibitor of proteosomes, caused inhibition of DPC repair, suggesting that the active removal of DPC in cells may involve proteolytic degradation of crosslinked proteins. XP-F cells showed somewhat higher sensitivity to formaldehyde, possibly signaling participation of XPF protein in the removal of residual peptide-DNA adducts. PMID: 10910961, UI: 20372597 Toxicol Vitr 2000 Aug;14(4):287-95 In vitro genotoxicity of ethanol and acetaldehyde in human lymphocytes and the gastrointestinal tract mucosa cells. Blasiak J, Trzeciak A, Malecka-Panas E, Drzewoski J, Wojewodzka M Department of Molecular Genetics, University of Lodz, 12/16, 90-237 Lodz, Banacha, Poland. januszb@biol.uni.lodz.pl The influence of ethanol and acetaldehyde on DNA in human lymphocytes, gastric mucosa (GM) and colonic mucosa (CM) was investigated by using the comet assay. All kinds of cells were exposed to ethanol and acetaldehyde in two regimens: the cells were incubated with either chemical and analysed or they were exposed first to ethanol, washed and then exposed to acetaldehyde and analysed. Lymphocytes were exposed to ethanol at final concentrations of 30 mM and acetaldehyde at 3 mM. GM cells were incubated with ethanol at 1 M and acetaldehyde at 100 mM. CM cells were exposed to ethanol at 10 mM and acetaldehyde at 100 mM. In combined exposure, the cells were subsequently exposed to ethanol and acetaldehyde at all combination of the concentrations of the agents. Ethanol caused DNA strand breaks, which were repaired during 4 hr, except when this agent was applied in GM cells at a concentration of 1 M. A dose-dependent decrease in the tail moment of all types of acetaldehyde-treated cells was observed. Similar results were obtained when a recognized DNA crosslinking agent, formaldehyde, was used. These results suggest that acetaldehyde may form crosslinks with DNA. These crosslinks were poorly repaired. CM cells showed the highest sensitivity of all cell types to ethanol than lymphocytes and GM cells. There were no differences in the sensitivity to acetaldehyde of all the cell types. Our results clearly indicate that ethanol and acetaldehyde can contribute to cancers of the digestive tract. PMID: 10906435, UI: 20368927 Mutat Res 2000 Jul 10;468(2):93-108 Validation of single cell gel assay in human leukocytes with 18 reference compounds. Frenzilli G, Bosco E, Barale R Dipartimento di Scienze dell'Uomo e dell'Ambiente, Universita di Pisa, Italy. r.barale@geog.unipi.it To validate the alkaline single cell gel (SCG) assay as a tool for the detection of DNA damage in human leukocytes, we investigated the in vitro activity of 18 chemicals. Thirteen of these chemicals (pyrene (PY), benzo(a)pyrene (BaP), cyclophosphamide (CP), 4-nitroquinoline-1-oxide (4NQO), bleomycin (BLM), methylmercury chloride (MMC), mitomycin C (MTC), hydrogen peroxide (HP), diepoxybutane (DEB), glutaraldehyde (GA), formaldehyde (FA), griseofulvin (GF), sodium azide (NA)) are genotoxic in at least one cell system, while five compounds (ascorbic acid (AA), glucose (GL), D-mannitol (MAN), O-vanillin (VAN), chlorophyllin (CHL)) are classified as non-genotoxic. In this in vitro SCG assay, PY, BaP and CP were positive with exogeneous metabolic activation (rat S9 mix) while 4NQO, BLM, MMC, MTC, hydrogen peroxide, and diepoxbutane were positive in the absence of metabolic activation. CHL and VAN were unexpectedly found to induce a dose-dependent increase in DNA migration. AA, GL, and MAN were negative in a non-toxic range of doses. GF gave equivocal results, while FA and GA increased DNA migration at low doses and decreased DNA migration at higher doses. This behaviour is consistent with the known DNA damaging and crosslinking properties of these compounds. These data support the sensitivity and specificity of this assay for identifying genotoxic agents. PMID: 10882888, UI: 20342076 Mutat Res 1999 Sep;437(2):151-63 Comparison of the spectra of genetic damage in formaldehyde-induced ad-3 mutations between DNA repair-proficient and -deficient heterokaryons of Neurospora crassa. de Serres FJ, Brockman HE Mammalian Mutagenesis Group, Laboratory of Toxicology, Systems Toxicology Branch, Environmental Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27703-27709, USA. deserres@niehs.nih.gov 919-541-3345 info The mutagenic effects of formaldehyde (FA) have been compared in DNA repair-proficient (heterokaryon 12) and DNA repair-deficient (heterokaryon 59) two-component heterokaryons of Neurospora crassa. The data from forward-mutation experiments were used to compare the spectra of FA-induced specific-locus mutations at two closely linked loci in the adenine-3 (ad-3) region and on the FA-induced inactivation of heterokaryotic conidia. Previous studies have demonstrated that specific-locus mutations at these two loci result from five major genotypic classes, namely two classes of gene/point mutations (ad-3A(R) and ad-3B(R)), and three classes of multilocus deletion mutations ([ad-3A](IR), [ad-3B](IR), and [ad-3A ad-3B](IR)). Genetic analysis of ad-3 mutants recovered from both heterokaryons after FA treatment demonstrates that predominantly gene/point mutations were found in H-12 (93.2% ad-3(R), 6.8% [ad-3](IR)) and a significantly higher frequency of multilocus deletion mutations in H-59 (62.8% ad-3(R), 37.0% [ad-3](IR)). The data from our experiments with FA on H-12 demonstrate and confirm the data from other assays that FA is a weak mutagen in this DNA repair-proficient strain. However, the data from our experiments with the DNA repair-deficient strain H-59 demonstrate that comparable concentrations of FA cause more pronounced inactivation of heterokaryotic conidia and, at the highest concentration tested, about a 35-fold higher frequency of ad-3 mutations. In addition, FA induced a 5.4-fold higher frequency of ad-3 mutations resulting from multilocus deletion mutation in H-59 than in H-12. Based on our earlier studies with X-ray-induced multilocus deletion mutations, it is this class of FA-induced ad-3 mutations that might be most expected to show deleterious heterozygous effects. The implications of the present data base from our experiments with Neurospora are that the mutagenic (and possibly the carcinogenic) effect of FA exposure might well vary in different human population subgroups. PMID: 10556619, UI: 20027293 Toxicol Appl Pharmacol 1999 Oct 1;160(1):86-100 Pharmacodynamics of formaldehyde: applications of a model for the arrest of DNA replication by DNA-protein cross-links. Heck H, Casanova M Chemical Industry Institute of Toxicology, Research Triangle Park, North Carolina 27709, USA. casaheck@beaufortco.com A variety of evidence suggests that formaldehyde (HCHO)-induced DNA-protein cross-links (DPX) are genotoxic as a result of their ability to arrest DNA replication. Although DPX can be removed and the DNA can be repaired, failure to remove the blockage prior to cell division or excision followed by incomplete repair could cause cell death or a mutation. To characterize the concentration and time dependence of this mechanism, a biologically based model for DNA replication in the presence of DPX was developed based on the assumptions that (1) DPX are formed randomly in the DNA and (2) a replication fork can advance up to but not past a DPX. Using a combination of Poisson and binomial statistics, a quantitative relationship between the amount of newly synthesized DNA and the concentration of DPX was derived, which predicts that the rate of DNA replication should decrease nonlinearly with increasing concentrations of DPX. Because the latter is a nonlinear function of the airborne concentration of HCHO, an inverse sigmoidal relationship is predicted between the rate of DNA replication and the concentration of inhaled formaldehyde. The model was parameterized using data derived from a study of the incorporation of [methyl-(14)C]thymidine monophosphate into the DNA of the nasal respiratory mucosa of Fischer-344 rats exposed to (3)HCHO and H(14)CHO (6 ppm, 6 h). The model was then applied to measurements of DNA replication in the nasal mucosa of experimental animals exposed to wide ranges of H(14)CHO (rats: 0.7, 2, 6, or 15 ppm, 3 h; rhesus monkeys: 0.7, 2, or 6 ppm, 6 h). The results indicate that, at airborne concentrations above 6 ppm in rats, there is a marked decrease (ca. 62% at 15 ppm) in the amount of newly synthesized DNA due to DPX formation during a single 6-h exposure to HCHO. The arrest of DNA replication at high HCHO concentrations could result in cytolethality or genotoxicity, both of which are critical factors in the induction of rat nasal cancer by HCHO. However, at concentrations below 2 ppm in monkeys or 1 ppm in rats, the decrease in the rate of DNA replication is predicted to be <1% after a 6-h exposure. This small decrease is probably undetectable using currently available techniques. The parameterized model suggests that the arrest of DNA replication by DPX is mainly a high-dose phenomenon and that at ambient exposure concentrations it is unlikely to be a major risk factor. PMID: 10502505, UI: 99434227 Risk Anal 2000 Apr;20(2):273-91 Air toxics and health risks in California: the public health implications of outdoor concentrations. Morello-Frosch RA, Woodruff TJ, Axelrad DA, Caldwell JC University of California-Berkeley, School of Public Health, Environmental Health Sciences Division 94720-7360, USA. rmf@uclink.berkeley.edu woodruff.tracey@epa.gov Caldwell.Jane@epamail.epa.gov Of the 188 hazardous air pollutants (HAPs) listed in the Clean Air Act, only a handful have information on human health effects, derived primarily from animal and occupational studies. Lack of consistent monitoring data on ambient air toxics makes it difficult to assess the extent of low-level, chronic, ambient exposures to HAPs that could affect human health, and limits attempts to prioritize and evaluate policy initiatives for emissions reduction. Modeled outdoor HAP concentration estimates from the U.S. Environmental Protection Agency's Cumulative Exposure Project were used to characterize the extent of the air toxics problem in California for the base year of 1990. These air toxics concentration estimates were used with chronic toxicity data to estimate cancer and noncancer hazards for individual HAPs and the risks posed by multiple pollutants. Although hazardous air pollutants are ubiquitous in the environment, potential cancer and noncancer health hazards posed by ambient exposures are geographically concentrated in three urbanized areas and in a few rural counties. This analysis estimated a median excess individual cancer risk of 2.7E-4 for all air toxics concentrations and 8600 excess lifetime cancer cases, 70% of which were attributable to four pollutants: polycyclic organic matter, 1,3 butadiene, formaldehyde, and benzene. For noncancer effects, the analysis estimated a total hazard index representing the combined effect of all HAPs considered. Each pollutant contributes to the index a ratio of estimated concentration to reference concentration. The median value of the index across census tracts was 17, due primarily to acrolein and chromium concentration estimates. On average, HAP concentrations and cancer and noncancer health risks originate mostly from area and mobile source emissions, although there are several locations in the state where point sources account for a large portion of estimated concentrations and health risks. Risk estimates from this study can provide guidance for prioritizing research, monitoring, and regulatory intervention activities to reduce potential hazards to the general population. Improved ambient monitoring efforts can help clarify uncertainties inherent in this analysis. PMID: 10859786, UI: 20317367 Ann Allergy Asthma Immunol 1999 Dec;83(6 Pt 2):618-23 Toxicologic considerations in the diagnosis of occupational asthma. Waddell, William "Bill" J. bwaddell@louisville.edu Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, Kentucky, USA. BACKGROUND: The consideration of dose for chemicals inducing occupational asthma is examined from the point of view of a toxicologist. Two widely used chemicals in industry, toluene diisocyanate (TDI) and formaldehyde, are used as examples of agents that are formally recognized by OSHA to cause occupational asthma. The Permissible Exposure Limit (PEL) of OSHA and the Threshold Limit Value (TLV) of ACGIH for TDI are identical and are in the range of values for which occupational asthma has been reported in some workers. The narrow range of exposure values for TDI in studies of workers with and without asthma is discussed and correlated with the background concentration of TDI in the ambient atmosphere. For formaldehyde, the PEL and TLV, in contrast, offer a wide margin of safety for the inducement of occupational asthma. CONCLUSION: From this disparity in exposure limits for TDI and formaldehyde, it is concluded that occupational exposure limits by agencies for specific chemicals do not provide a reliable indication of the concentration of a chemical that is necessary to produce occupational asthma. The need for a better appreciation of dose response, particularly relative to background, ambient levels, in the evaluation of occupational asthma is emphasized. PMID: 10619332, UI: 20084350 Toxicol Environ Health 1999 Jul 23;57(6):431-42 Activity of cathepsin G, elastase, and their inhibitors in plasma during methanol intoxication. Skrzydlewska E, Szmitkowski M, Farbiszewski R Department of Analytical Chemistry, Medical University, Bialystok, Poland. skrzydle@amb.ac.bialystok.pl Methanol oxidation in the liver is accompanied by formation of formaldehyde and free radicals. These compounds can react with biologically active proteins, including proteolytic enzymes and their inhibitors. The activity of cathepsin G and elastase and their inhibitors such as alpha-1-antitrypsin and alpha-2-macroglobulin in plasma of rats given methanol orally in doses of 1.5, 3, and 6 g/kg was investigated for 7 days. The activity of cathepsin G and elastase was increased from 12 h to 5 d, proportionally to methanol dose. At the same time, activity of their inhibitors was reduced. Methanol ingestion in humans caused changes in activities of proteases and their inhibitors with similar direction as in rats. These changes in activity of proteases and their inhibitors produce significant disturbances in proteolytic-antiproteolytic balance after methanol administration. PMID: 10478824, UI: 99405938 Pathol Res Pract 2000;196(3):193-8 Formaldehyde neurotoxicity in animal experiments. Pitten FA, Kramer A, Herrmann K, Bremer J, Koch S Institute of Hygiene and Environmental Medicine, [Institut fur Hygiene und Umweltmedizin] Ernst-Moritz-Arndt-University, Greifswald, Germany. pitten@rz.uni-greifswald.de The aim of this study was to determine whether the inhalation of formaldehyde has a neurotoxicological impact. Forty Wistar rats (Lew.1/K) were trained to find food in a maze within a particular time. When all animals were at an equal level, 13 rats inhaled 2.6 ppm and 13 others inhaled 4.6 ppm formaldehyde 10 min/d, 7 d/week for 90 d. The control group comprised 14 animals inhaling water steam according to the same exposure pattern. During the exposure period and the post-trial observation stage (30 d), the time required to find the food and the number of mistakes made on the way were recorded. Between the animals exposed to formaldehyde and the control group a statistically significant difference for both parameters was observed (p < 0.05). The animals exposed to formaldehyde needed more time and made more mistakes than the animals of the control group while going through the maze. The results underline the necessity for a systematic observance of precautions in case of occupational or dwelling-related formaldehyde exposure, and allow us to classify formaldehyde as "probably neurotoxic". Further investigations are required to assess the neurotoxicologic impact of subchronic formaldehyde exposure. PMID: 10729924, UI: 20194117 Human & Experimental Toxicology (2000) 19, 360-366. Toxicity of ingested formalin and its management. Pandey CK, Agarwal A, Baronia A, Singh N Department of Anaesthesiology and Critical Care Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India. ckpandey@sgpgi.ac.in Formaldehyde is a physiological intermediary metabolite taking part in many biological process in the body. It is a constituent of many items of daily use, including foods. It is also used in medicine for treatment of some conditions. A 40% solution of formaldehyde in water is known as formalin. Formalin is irritating, corrosive and toxic and absorbed from all surfaces of the body. Ingestion is rare because of alarming odour and irritant effect but documented in accidental, homicidal or suicidal attempts. Ingestion can lead to immediate deleterious effects on almost all systems of the body including gastrointestinal tract, central nervous system, cardiovascular system and hepato-renal system, causing gastrointestinal hemorrhage, cardiovascular collapse, unconsciousness or convulsions, severe metabolic acidosis and acute respiratory distress syndrome. No specific antidote is available. Treatment of toxicity is supportive care of the various organ systems. Multidisciplinary approach is required for proper management. PMID: 10962510 ****************************************** Rich Murray, MA Room For All rmforall@att.net 1943 Otowi Road, Santa Fe NM USA 87505 505-986-9103 http://groups.yahoo.com/group/aspartameNM/messages for 863 posts http://groups.yahoo.com/group/aspartameNM/message/861 brief summary http://groups.yahoo.com/group/aspartameNM/message/862 long summary http://groups.yahoo.com/group/aspartameNM/message/860 RTM: FDA: objections to neotame approval (Section A) 8.4.2 rmforall Rich Murray: Serious symptom syndrome summary: Aspartame (NutraSweet, Equal, Canderel, Benevia) is reported by scientific studies and case histories to be toxic: * headaches * many body and joint pains (or burning, tingling, tremors, twitching, spasms, cramps, or numbness) * fever, fatigue * "mind fog", "feel unreal", poor memory, confusion, anxiety, irritability, depression, mania, insomnia, dizziness, slurred speech, ringing in ears, sexual problems, poor vision, hearing, or taste * red face, itching, rashes, burning eyes or throat, dry mouth or eyes, mouth sores * hair loss * obesity, bloating, edema, anorexia, poor or excessive hunger or thirst * breathing problems * nausea, diarrhea or constipation * coldness * sweating * racing heart, high blood pressure, erratic blood sugar levels * seizures * birth defects * brain cancers * addiction * aggrivates diabetes, autism, ADHD, and interstitial cystitis (bladder pain). Almost all are typical of chronic methanol-formaldehyde toxicity: for detailed review http://www.dorway.com/barua.html Journal Of The Diabetic Association Of India 1995 Vol. 35, No. 4. Emerging Facts About Aspartame Dr. J. Barua (ophthalmic surgeon), Dr. Arun Bal (surgeon) (79 references) barua@giasbm01.vsnl.net.in "...the total amount of methanol absorbed will be approximately 10% of aspartame ingested. An EPA assessment of methanol states that methanol "is considered a cumulative poison due to the low rate of excretion once it is absorbed." The absorbed methanol is then slowly converted to formaldehyde..." "Reaction of formaldehyde with DNA has been observed, by spectrophotometry and electron microscopy, to result in irreversible denaturation." http://groups.yahoo.com/group/aspartameNM/message/830 RTM: Tholen: Diet Coke has 5 ppm formaldehyde from aspartame 5.29.2 rmforall For 6 cans of diet soda, this is 5 times the daily limit of 1 PPM for formaldehyde in drinking water, set by the EPA. ***********************************************************