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Rich Murray: 18 recent formaldehyde toxicity [Comet assay] abstracts 6.25.1 rmforall

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  • Rich Murray
    Rich Murray: 18 recent formaldehyde toxicity [Comet assay] abstracts 6.25.1 rmforall [ See also, re formaldehyde neurotoxicity:
    Message 1 of 1 , Jun 25, 2001
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      Rich Murray: 18 recent formaldehyde toxicity [Comet assay] abstracts
      6.25.1 rmforall

      [ See also, re formaldehyde neurotoxicity:
      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@...,
      "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
      Dr. Marià Alemany Fac. Biologia Tel.: (93)4021521, FAX: (93)4021559
      alemany@... bioq@... josefer@...
      rafecas@... remesar@...
      Sra. Carme Trocho Fac. Biologia Tel.: (93)4021544, FAX: (93)4021559

      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@...
      ttephly@... 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"
      Aspartame Toxicity Information Center Mark D. Gold
      www.HolisticMed.com/aspartame 603-225-2100
      mgold@... 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@..., 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@... , 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.

      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.

      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.

      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@...

      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@... 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.

      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@...

      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@...
      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@...

      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.

      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.

      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@...
      1943 Otowi Road, Santa Fe, New Mexico 87505 USA

      M.I.T. (physics and history, BA, 1964), Boston U. Graduate School
      (psychology, MA, 1967): As a concerned layman, I want to clarify the
      aspartame toxicity debate.

      long 40K summary

      Excellent 5-page review by H.J. Roberts in "Townsend Letter",
      Jan 2000, "Aspartame (NutraSweet) Addiction"
      http://www.dorway.com/tldaddic.html http://www.sunsentpress.com/
      H.J. Roberts, M.D. HJRobertsmd@... sunsentpress@...
      Sunshine Sentinel Press 6708 Pamela Lane West Palm Beach, FL 33405
      800-814-9800 561-588-7628 561-547-8008 fax
      1038 page text "Aspartame Disease: An Ignored Epidemic"
      published May 30 2001 $ 85.00 postpaid data from 1200 cases
      http://www.aspartameispoison.com/contents.html 34 chapters

      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); "mind fog", "feel unreal", poor memory,
      confusion, anxiety, irritability, depression, mania, insomnia,
      dizziness, slurred speech, ringing in ears, sexual problems, nausea,
      seizures, poor vision, hearing, or taste; fever, fatigue; red face,
      itching, rashes, burning eyes or throat, dry mouth or eyes, mouth
      sores; hair loss; obesity, bloating, edema, poor or excessive hunger
      or thirst, anorexia; coldness; diarrhea or constipation; breathing
      problems; racing heart, high blood pressure, erratic blood sugar
      levels; sweating; birth defects; brain cancers; addiction;
      aggravates autism, ADHD, and interstitial cystitis (bladder pain).

      Almost all chronic aspartame symptoms 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@...
      "...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."
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