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

[Guest guest]

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

6.25.1 rmforall

[ 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

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. rio Pardo, Dra. Immaculada Rafecas,

Sr. Jordi Virgili, Dr. Xavier Remesar, Dr.

Fernandez-,

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

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 R. Tephly 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 "

http://www.holisticmed.com/aspartame/abuse/methanol.html

Aspartame Toxicity Information Center Mark D. Gold

www.HolisticMed.com/aspartame

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, Meltzer (or Melzer), and ph

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.

guenter.speit@...

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, A. ; Zhitkovich, Anatoly

Department of Pathology and Laboratory Medicine,

Brown University, Box G-B511, Providence, RI 02912, USA.

_Quievryn@...

Anatoly_Zhitkovich@...

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@...

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@... 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® and ad-3B®), 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®, 6.8% [ad-3](IR)) and a

significantly higher frequency of multilocus

deletion mutations in H-59 (62.8% ad-3®, 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@...

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@...

woodruff.tracey@...

Caldwell.Jane@...

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, " 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.

pitten@...

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@...

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

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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.

http://groups.yahoo.com/group/aspartameNM/message/618

long 40K summary

Excellent 5-page review by H.J. in " Townsend Letter " ,

Jan 2000, " Aspartame (NutraSweet) Addiction "

http://www.dorway.com/tldaddic.html http://www.sunsentpress.com/

H.J. , M.D. HJmd@... sunsentpress@...

Sunshine Sentinel Press 6708 Pamela Lane West Palm Beach, FL 33405

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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