Posted: 08 June 2012

WC Monte finally got secret FDA memo 37 years after Searle Co. labs found birth defects in rabbits from aspartame (methanol, becomes formaldehyde via ADH1 enzyme within human cells) and its phenylalanine: Rich Murray 2012.06.02
http://rmforall.blogspot.com/2012/06/wc-monte-finally-got-secret-fda-memo-37.html
http://health.groups.yahoo.com/group/aspartameNM/message/1650

Monte, Woodrow C. (2011-12-30). While Science Sleeps (Kindle Locations 5542-5612). Amazon. Kindle Edition.

Free Chapter 12 "Autism and Other Birth Defects" with 100 free online full text pdf medical research references

http://www.whilesciencesleeps.com/While%20Science%20Sleeps%20-%20Chapter%2012%20(ref).pdf

[ start of selection ]

Hidden Memo Revealed

In an article published in 1985 warning about potential health dangers posed by the methanol from aspartame, 1 I stated that the scientific literature contained no studies addressing the critical question as to whether aspartame or methanol would cause birth defects.

I was incorrect in saying that, but only because I was purposefully prevented from seeing a key FDA memo dated September 11, 1978 describing the details of birth defects and serious developmental brain damage found in the offspring of laboratory rabbits whose mothers had been fed aspartame during pregnancy.

This memo and the research data it describes were kept secret for over thirty years until January of 2011, when the memo was finally released as the result of a Freedom of Information request.

Figure 12.1

In that detailed US Food and Drug Administration memo, which was authored by Dr. Thomas Collins of the Animal Toxicology Branch to the Chief of the Food Additive Evaluation Branch, Collins reports the disturbing discovery of “significant” multiple neural tube (and other) birth defects in rabbit pups whose mothers were fed aspartame during the course of several different toxicity studies done by both G.D. Searle and Hazelton Laboratories between 1974 and 1975.

It appeared to be Dr. Collins’ assignment to evaluate the studies, and his conclusions were stunning:

“In both rabbit studies, aspartame appeared to cause birth defects.” 677

To my knowledge, this book is the first time this memo has been discussed publicly.

Like most of the scientific community, I had no idea that aspartame had tested positive for producing neural tube birth defects.

It was not until January 16, 2011 that this “smoking gun” memo came into my possession.

This is one of many important memos that were removed from the aspartame Docket File before I was allowed to review it in 1983.

Figure 12.1 is an image of the ticket that gave me access to the FDA’s “complete” collection of aspartame test data and it does confirm that memos had been removed.

Importance of the Collins Memo: Government Collusion Uncovered

Of the several million chemicals, pesticides and herbicides now in use, only an exceedingly small percentage have ever tested positive for causing birth defects.

Barely 800 chemicals are known teratogens, producing birth defects in laboratory animals, and “only about twenty of these are known to cause birth defects in the human.” 466

Nature has numerous methods, the exact details of which are still unknown to us, for protecting the developing infant.

As a last resort she will often call upon the macrophages to destroy a fetus that becomes unfit for life well before the time of birth, in a process called resorption.

This is why the occurrence of a deformed fetus in the testing of any chemical is a rare phenomenon and would normally raise a “red flag” to any scientist concerned with public safety.

It would be particularly significant if that chemical was being tested for use as a food additive.

It was not until 20 years after the 1978 FDA memo that methanol was first tested again and found to cause neural tube birth defects in rats 626 and eventually in many other species of laboratory animal. 104

To this day aspartame is not listed as a teratogen because the FDA and G.D. Searle covered up the tests that were performed in 1974 and 1975.

Worse yet, during the time they were in possession of this proof of aspartame’s teratogenicity, Searle paid to have a faux scientific paper written by one of their employees published in an international fertility journal (which is read by many gynecologists and pediatricians) stressing the safety of aspartame and falsely proclaiming that “aspartame posed no risk” from consumption during pregnancy. 100

U. S. Environmental Protection Agency Admits Methanol Is a Probable Cause of Birth Defects

Although it was many years before the details could be determined with any certainty, it did not take a great deal of time for exposure to aspartame to adversely affect the rate of birth defects in the United States and its trading partner, the United Kingdom. 738

The reason for this is clear, now that the Center for the Evaluation of Risks to Human Reproduction of the U.S. National Institutes of Health has determined methanol to be a potential developmental toxicant (teratogen) in humans.

In an extensive multi-year review of the toxicity of methanol, finished in 2009, the Center reported numerous birth defects in animals exposed to methanol during pregnancy. 627

Stated continuously throughout their 500 page report is the mantra that “humans are much more sensitive to methanol toxicity than laboratory animals.”

“… The inhalation of methanol by pregnant rodents throughout the period of embryogenesis induces a wide range of concentration-dependent teratogenicity and embryolethal effects. Treatment-related malformations, primarily extra or rudimentary cervical ribs and urinary or cardiovascular defects, were found in fetuses of rats … Increased incidences of exencephaly and cleft palate (neural tube birth defects) were found in the offspring of … and an increasing incidence of resorptions. Reduced fetal weight was observed… included neural and ocular defects, cleft palate, hydrocephalus and limb anomalies.” 685
[The very same birth defects found by G.D. Searle Co. in rabbits in their labs in 1974]

Tragically, the US Food and Drug Administration (FDA) kept the Collins memo secret from the Center for the Evaluation of Risks to Human Reproduction (CERHR) throughout its entire two-year investigation of methanol’s potential to cause birth defects.

This was done despite the fact that both the FDA and the CERHR are part of the same public agency -- the Department of Health and Human Services.

The final CERHR report published in September of 2009 mentions aspartame no fewer than 93 times and raises many questions about its potential for teratogenicity.

These questions could have been answered by giving the committee access to the Collins memo and other studies to which the Collins memo refers that are still hidden in the vaults of the FDA. 627

It is noteworthy that two of the 11 voting members of the expert panel, both representing the US Environmental Protection Agency, refused to sign off on the summary of the CERHR methanol report and, in fact, initiated a formal dissent that warned of “a greater risk to vulnerable populations of pregnant women” than the compromised final report of the CERHR expert panel alleged. 551

The most senior of the dissenting scientists, J. Michael Davis, Ph.D. reveals in his strongly worded five page formal dissent 551 that “factual errors and omissions” prompted him not to sign the final report.

He goes on: “As just one example, the missing pages from the 1986 NEDO (New Energy Development Organization) report, which I identified and provided to the CERHR contractor, were evidently never provided to members of the Panel. The pages in question included a table showing reductions in brain weight in a two-generation rat study that had been replicated in a special ancillary study…If nothing else, omission of this information creates the impression that the Panel failed to consider all relevant information.” (I must point out here that autistic children often present with a reduced brain size at birth. 739)

The other courageous dissenter, Dr. Stanley Barone, a research biologist from the Neurotoxicology Division of the US EPA, explains that “the panel could not agree about the significance of the outcomes of the primate study of Burbacher et. al. 92”

He goes on: “Again, I reiterate that I do not think that the process that the panel went through for the evaluation of methanol adequately addressed susceptible populations concerns. …e.g., pregnant women with genetic polymorphisms that limit detoxification capacity of methanol.” 551

These strong statements from the two most qualified environmental scientist members of the committee, who also happen to be civil servants, should catch your attention because it seldom happens.

I listened patiently during the years that this important committee was scuffling amongst themselves to come to the conclusion which must have been so very obvious to everyone from day one: “Methanol is a potential cause of human birth defects.”

The fact that this statement is not considered a strong enough warning in the minds of the best scientists on the committee means, in this day and age, that the statement should have read, “Methanol causes birth defects and we need to learn more.”

The tragedy is that by keeping this information secret for all these years, the FDA and the EPA have become culpable and, to my mind, complicit in allowing companies like [ Donald ] Rumsfeld’s G.D. Searle and Monsanto companies, and now the Ajinimoto company of Japan, to profit from producing and selling a product that has tested positively to damage the brains of the unborn.
[End of selection]

http://www.whilesciencesleeps.com/pdf/677.pdf

677. Collins TFX. Memorandum: Aspartame shown to cause neural tube birth defects in the New Zealand rabbit, an animal very resistant to methanol poisoning. Freedom of information: Department of Health Education and Welfare, Food and Drug Administration; 1978.

[Finally released January 16, 2011 -- original research final report dated October 8, 1974, 37 years ago...]

[Rich Murray: typos corrected, and line spacing added to increase readability in this poorly typed manuscript]

MEMORANDUM
DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE:
PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION

TO:
Charles J. Kokoski, Ph.D. DATE September 11, 1978
Chief. Food Additives Evaluation Branch, HFF-185

FROM:
Thomas F.X. Collins, Ph.D.
Whole Animal Toxicology Breach, HFF-155

SUBJECT:
Aspartame (SC-18862).
Review of four studies submitted by G.D. Searle as entries to Food Additive Master File 134, in response to your memo of September 1, 1978.

1. E--79. SC-18862:
Segment II, an evaluation of the teratogenic potential in the rabbit.
Final report.
Hazleton Laboratories, Inc., Vienna, Virginia, October 8, 1974.

Procedure.
New Zealand white rabbits were given a 5% or 15% aqueous suspension of aspartame in I% aqueous Tween-80 by oral intubation twice per day from day 6 through day 18 of gestation. The dosage given was 0.75 g/kg/day for the low dosage and 2.0 g/kg/day for the high dose.

The control group received a I% aqueous solution of Tween-80 by oral intubation twice daily during the same days of gestation in a volume equal to that received by the highest dose level.

The study was done in three replicates (sub-groups A, B, C).
The number of animals per subgroup ranged
from 10 to 12 for the controls,
from 11 to 14 for the low level,
and 28 to 38 for the high level.

Control females in each group were paired on a g/kg basis with the appropriate number of group-3 does from the corresponding subgroup which consumed the least amount of the diet on the preceding day (same day of gestation).

To accomplish pair feeding, the control females in each subgroup were inseminated 24 hours following insemination of animals assigned the corresponding high level group.

Palr feeding began on day 6 and continued until sacrifice at day 29.

During treatment, the animals were fasted 8-9 hours (1.5-2 hours preceding the first daily dose and ending after completion of the second dose).

Results.
Mortality rate was slightly increased at both dose levels but this was not related to dose.

Conception rates showed a dose-related decrease.

Both experimental groups gained weight during the period of treatment while the controls actually lost weight.

The pre- treatment food consumption rates were similar for the control and treatment groups.

During treatment, the treated groups consumed significantly more food than the controls.

Following treatment, the controls consumed slightly more food than during the treatment period, while the treated groups consumed slightly less, but still the treated groups consumed significantly more food than the controls.

There appeared to be a slight increase in pre-implantation loss at the high dose level.

There appeared to be a decrease in the mean number of live fetuses and an increase in the mean number of resorption sites at the high dose level.

Statistics were only done on the combined data.

If statistics were done on the subgroups, significant effects on these parameters might be noted.

There was no increase in the number of does with implantation scars, resorption sites, or dead fetuses.

Mean fetal weight was significantly increased at the low dose level (0.75 g/kg) but was not affected at the high level.

There appeared to be no effect on fetal length.

At the high dose level, there was an increase in the number of fetuses with abnormalities and an increase in the number of litters affected.

No abnormalities were observed in the control animals (19 litters).

At the low dose level, 1 of 198 fetuses (24 litters) showed gastroschisis with associated rotation of hind-limbs, rotation of the eye, and other anomalies.

At the high dose level, 7 of 343 fetuses (6 litters out of 45) showed major and minor anomalies consisting in part of: bi-clefted lip, cleft palate, fused mandible, short maxillary bones,
fusion and misalignment of caudal vertebrae, reduced ossification of thoracic and caudal vertebrae and phalanges, hydrocephalus, missing ribs, and ectrodactyly.

Problems.

1. The exact mechanism of the pair-feeding schedule is not clear.

2. Eighteen fetuses at the high level were too small to be processed, [ ! ] hence the evaluation of these fetuses is not available.

Rigorous pair feeding was certainly a factor.

E-83. SC-18862
Placebo: An evaluation of embryotoxic and teratogenic potential of specially prepared pelleted diet in the rabbit.
Searle Laboratories,, October 1974.

Procedure.

This study was done to test the diet used in a previous segment II rabbit study conducted at Searle and Hazleton Laboratories. A commercially available diet from the same manufacturer served as the control. Sixty New Zealand white female rabbits approximately 9 months old were given one of the following diets: commercial control (10 animals), Searle control (25 animals), and Hazleton control (25 animals). The animals had a mean body weight of 3.8 kg. Searle and Hazleton diets were offered ad libitum to the appropriate groups of animals from the morning of gestation day 6 to the morning of gestation day 19. Commercial diet was given prior to and subsequent to this period. The animals were sacrificed near term (day 28) and the uterine contents examined.

The diets were analyzed for moisture content, aflatoxins, aerobic bacteria, yeasts, and molds.

Results.
Hazleton and Searle diets showed less moisture due to additional drying times these diets had prior to the pelleting process. There was also an increase in the amount of detectable yeasts and molds in the Searle and Hazleton diets.

Maternal survival, fertility, body weight, and food consumption were comparable among the three groups. In fact, animals on Searle and Hazleton diets gained slightly more weight than those on the commercial control diets.

There was a decrease in mean litter size between [from] the commercial diet and [to]0 both the Searle and Hazleton control diets, as well as an increase in resorptions.

The authors of the report state that an unusually large litter size vas found in the commercial control diet, and that the mean litter size in the special diets is similar to that seen in historical rabbit data.

The number of pregnant females with resorption sites and the mean number of resorption sites per litter were increased in the special diet groups.

Weight and crown-rump lengths to both sexes for both special diets were increased over the commercial control diet.

Two gross abnormalities appeared in the Hazleton diet animals, one exencephaly and one cleft palate.

No gross abnormalities were noted in the other two diets.

One minor gross malformation was noted in each of the commercial control and Searle control diets; no minor malformations were noted in the Hazleton control diet.

The total incidence of fetuses with major malformations observed during external, soft-tissue, and skeletal examlnation was: 0 of 64 fetuses in the commercial control diet (7 litters), 2 of 120 fetuses in the Searle control diet (2 of 19 litters), and 12 of 151 fetuses in the Hazleton control diet (5 of 20 litters).

Soft-tissue examination revealed no additional fetuses with minor malformations.

The incidence of fetuses with minor malformations detected during skeletal examination are: 0 of 34 fetuses in the commercial control diet (7 litters), 4 of 62 fetuses in the Searle control diet (3 of 19 litters) and 6 of 79 fetuses in the Hazleton control diet (4 of 20 litters).

In the commercial control diet group, the sole malformation observed was one fetus with a short tail.

In the Searle control. diet, there were two fetuses with bilateral folding of the retina, 4 fetuses with fused 4th and 5th sternebrae, and one fetus with bilateral flexure of the fore- and hind-limbs.

In the Hazleton control diet, the skeletal anomalies seen were fused sternebrae (5) and poorly ossified skull bones (1).

Other anomalies seen in the Hazleton animals were bilateral folding of the retina (7), perforation of the interventricular septum (1), agenesis of the kidney and ureter (1), hydrocephalus (3), and cleft palate (1).

Problems.

1. The age of the diets is unknown.
   
2. The exact treatment of the diets at the two laboratories is unknown.
   
3. There was a small number of control animals.

The greatest number of abnormalities was produced with the Hazleton diet.

E-89. SC-18862:
An evaluation of embryotoxic and teratogenic potential in the mouse. Searle Laboratories, July 1975.

Procedure.
A Segment-II study was done on dietary aspartame using Charles River CD-1 albino mice 65-75 days old. Thirty-six females were assigned to each of 4 groups with an intended daily dose level of 0, 1.0, 2.0, or 4.0 g/kg, but the animals actually received approximately 40% more than the intended dose (1.4, 2.7, and 5.7 g/k, respectively). The compound was given on days 6-15 of gestation. The animals were sacrificed on day 18.

Results.
All females survived to day 18. There was a slight decrease in conception rate at the 4.0 g/kg level, but this was not significant. There was no compound-related effect on food consumption. There was no effect on the number of totally resorbed litters, mean litter size, number of resorption sites per litter, mean fetal body weight, or mean fetal length.

The incidence of major malformations was the following: 1 of 250 fetuses in the control group (1 of 25 litters), 0 of 251 fetuses of the low dose group (24 litters), 1 of 261 fetuses of the medium dose group (1 of 25 litters), and 0 of 204 fetuses of the high dose group (20 litters).

The control fetus with abnormalities had a hypoplastic 4th thoracic vertebral centrum.

The fetus from the medium dose group had exencephaly, cleft palate, and bilaterally open eyes.

Skeletal variants were noted, but there was no statistically significant difference which could be related to dosage.

Conclusion.
No compound-related teratogenic affects were detected in mice at dose levels up to 4.0 g/kg.

E-90. SC-18862:
An evaluation of embryotoxic and teretogenic potential in the rabbit; Searle Laboratories, July 1975.

Procedure.
New Zealand white female rabbits approcimately 8 months of age were randomly distributed among the following groups: 0, 0.5, 1.0, or 2.0 g/kg aspartame, or 0.82 g/kg L-phenylalanine (L-phen), [same as in 1.64 g/kg aspartame = 50%] or 1.10 g/kg L-aspartic acid (L-asp). [same as in 2.75 g/kg aspartame = 40%] The compound and/or vehicle was intubated twice per day in 2 doses, separated by at least 3 hours, on days 6-18 of gestation. The compounds were suspended in a solution of 0.5% carboxymethyl cellulose and 1% Tween-80.

L-phen and L-asp, dietary amino acids, are the principal constituents of aspartame.

Food consumption was recorded daily during gestation. Body weights were recorded on days 0, 3, 6, 10, 13, 15, 18, 22, and 28. Cesarean sections were done on day 28, and standard teratological observations were made. Approximately 50 rabbits per dose were used.

Results.
Survival rate of the dams was not affected by aspartame or the 2 dietary amino acids.

Conception rate was slightly decreased at the high

dose level, and the proportion of pregnancies vhich terminated in abortion was significantly greater than the control group. From day 13 to day 28, the average body weight of the females given the high dose level was significantly less than the weight of the controls.

Mean food consumption for control, 0.5, and 1.0 g/kg aspartame decreased to 75-90% of the daily pretreatment values.

Daily food consumption in the high dose group decreased to 25-35% of pretreatment values and was significantly less than the control values.

After treatment, i.e., by day 22 of gestation, food consumption in the high dose group was back to normal.

Food consumption in the L-phen females decreased to 50-60% of the pretreatment mean and significantly less than the control animals on each day of treatment.

Food consumption. returned to normal on day 20.

A decrease in the number of litters having completely viable fetuses was noted at the high level aspartame and with L-phen.

The number of litters completely resorbed and the number of resorption sites per litter were increased at the high dose Level of aspartame.

Mean litter size was not affected by aspartame dosage.

Fetal body weight and crown-rump lengths were significantly decreased in both sexes at 2.0 g/kg aspartame and L-phen

. The number of litters containing pups with grossly visible abnormalities was increased in the 2.0 g/kg aspartame and L-phen groups.

Cleft palate appeared to be significantly increased at the high dose level of aspartame.

There was a significant increase in the number of rabbits with an extra pair of ribs, as well as a significant decrease in ossification of the second sternebral center, increased absence of the 6th sternebral center, increase in unossified metacarpals, and an increase in unossified tarsals.

Conclusion.
There were deleterious effects at the high dose level of aspartame, 2.0 g/kg, in rabbits.

Dosage up to 1.0 g/kg/day did not appear to affect pregnant rabbits.

[They did not present that their evidence shows birth defects from L-Phenylalanine...]

General conclusions.

1. Aspartame appeared to be non-teratogenic in the mouse feeding study at dose levels of 1.4, 2.7, and 5.7 g/kg.

2. In both rabbit studies, aspartame appeared to cause birth defects at the high level (2 g/kg).

3. In the comparison of diets used in rabbit studies at Sear/e and Hazleton, more abnormalities were seen in the special diets than in the control diets but the treatment and the age of the diets are not given.

"The Panel concluded that methanol is the most likely proximate teratogen;

however, the biological basis by which it induces such effects remains unknown.

The Panel assumed the available rodent data were relevant for humans.

The Panel has minimal concern that methanol exposures resulting in low (<10 mg/l) blood methanol concentrations may result in developmental toxicity in humans.

These methanol concentrations have been associated with consumption of a common American diet and with work exposures that are below U.S. occupational exposure limits."

"Alcoholic beverages contain methanol at concentrations ranging from 6 to 27 mg/l in beer, 96 to 329 mg/l in wine [1,13], and up to 1500 mg/l in some neutral spirits [1]. Taucher et al. [14] demonstrated an increase in the breath methanol levels of subjects consuming 100 ml brandy; however, the Panel notes that the study does not provide useful information since the correlation between breath and blood methanol was not determined. In addition to natural sources of methanol in the diet, the public is also exposed to methanol through two direct food additives: aspartame and DMDC. Aspartame (l-aspartyl-lphenylalanine methyl ester) is an artificial sweetener. It is a dipeptide that is primarily comprised of phenylalanine and aspartic acid [15]. When ingested, about 10% by weight of aspartame is hydrolyzed to free methanol, which is then available for absorption [1]. DMDC is a yeast inhibitor used in tea beverages, sports drinks, fruit or juice sparklers, wines, and wine substitutes [16–18]. DMDC is unstable in aqueous solutions (beverages) and primarily breaks down to methanol and carbon dioxide [16]. Theoretically, full hydrolysis of one mole of DMDC yields two moles of methanol and two moles of carbon dioxide. On a weight basis, 100 mg of DMDC in a beverage would theoretically produce 48 mg methanol." [dimethyl dicarbonate] [They did not mention that cigarette and wood smoke, and fruits juices vegetables heated in sealed cans and jars, some fresh coffees, and spoiled fermented and smoked foods are potent sources of methanol.]

627. Shelby M.
NTP-CERHR Expert Panel report on the reproductive and developmental toxicity of methanol.
Reproductive Toxicology 2004;18:303-90.
88 pages, 170 references
http://www.whilesciencesleeps.com/pdf/627.pdf

"5.3. Overall conclusions

The Expert Panel recognized the need to consider species differences in methanol metabolism and toxicity in its evaluation of the risk to reproduction posed by methanol exposure in humans.

The Expert Panel agreed that blood methanol concentrations provide a useful dose metric for the comparison of results among various studies.

There are sufficient pharmacokinetic data to determine blood methanol concentrations in rodents associated with adverse reproductive and developmental effects.

Mean maternal blood methanol concentration observed in mice following inhalation exposure to 1000 ppm methanol for 7 h per day on gd 6–15 (i.e. the fetal NOAEL for teratogenicity) was 97 mg/l.

Mean maternal blood methanol concentration observed in mice following inhalation exposure to 2000 ppm methanol for 7 h per day on gd 6–15 (i.e. the fetal LOAEL for teratogenicity) was 537 mg/l.

In humans, achievement of such a blood methanol concentration has resulted in formate accumulation, metabolic acidosis, ocular toxicity, and other signs of methanol toxicity.

These observations suggest that there may be overlap between exposures resulting in clinical signs of acute toxicity and those that might result in developmental toxicity in humans.

The toxicity data available to the Panel that was collected in monkeys provide suggestive but insufficient evidence that adverse developmental effects may occur in primates exposed by inhalation to methanol at maternally nontoxic doses.

The Panel’s confidence in these data may have been strengthened had statistical analyses that adjust for multiple testing been applied to the data.

The Expert Panel concludes that there is insufficient evidence to determine if the human fetus is more or less sensitive than the most sensitive rodent species (i.e. mouse) to methanol teratogenesis.

Moreover, other factors (e.g. genetic polymorphisms in key metabolizing enzymes, maternal folate status) that alter methanol metabolism may predispose some humans to developmental toxicity at lower blood methanol concentrations (<100 mg/l).

This caveat is especially important since the Expert Panel recognized that there are limited human exposure data for pregnant women and other potentially susceptible subpopulations.

The Expert Panel concluded that developmental toxicity was the most sensitive endpoint of concern with respect to evaluating the risk to reproduction posed by methanol exposure in humans.

In particular, the data obtained from rodent studies indicate that the gastrulating and early organogenesis-stage embryo is particularly sensitive to the adverse developmental effects of methanol.

The Panel concluded that methanol is the most likely proximate teratogen; however, the biological basis by which it induces such effects remains unknown.

The Panel assumed the available rodent data were relevant for humans.

The Panel has minimal concern that methanol exposures resulting in low (<10 mg/l) blood methanol concentrations may result in developmental toxicity in humans.

These methanol concentrations have been associated with consumption of a common American diet and with work exposures that are below U.S. occupational exposure limits.

• The Panel has concern that methanol may be a developmental toxicant in pregnant women following exposure to high levels of methanol.

• The Panel has negligible concern that methanol may be a male reproductive toxicant in humans under dietary conditions or occupational exposure that result in blood methanol concentrations <10 mg/l. However, there were not sufficient data to rule out the possibility that high, acutely toxic doses of methanol might affect male reproduction.

• The Panel determined that the data are insufficient to assess whether or not methanol is a reproductive hazard in females."

Name: J. Michael Davis
Job Title: Senior Science Advisor, National Center for Environmental Assessment, U.S. Environmental Protection Agency's Office of Research and Development
Organization: U.S. Environmental Protection Agency
Contact: Phone: 919.541.4162
Bio: Dr. J. Michael Davis is a Senior Science Advisor with the National Center for Environmental Assessment in the U.S. Environmental Protection Agency's Office of Research and Development at Research Triangle Park, North Carolina. He received his Ph.D. from Duke University in 1973, held postdoctoral fellowships at the University of Oxford, England and the University of North Carolina at Chapel Hill, served as a Research Associate and taught at Duke University,and has been with EPA since 1979. He initiated and led the development of the EPA case studies of Nanoscale Titanium Dioxide in Water Treatment and in Topical Sunscreen and of Nanoscale Silver in Disinfectant Spray,as well as associated “Nanomaterial Case Studies Workshops” in September2009 and January 2011. He has also been leading the development and use of Comprehensive Environmental Assessment for emerging technology issues.
Meetings Attended: Joint Special Meeting of The Toxicology Forum/Regulatory Governance
Initiative: Nanoparticles:Tools for Toxicology

Brown Dzubow, R., Makris, S., Siegel Scott, C. and Barone, S. Rebecca Brown Dzubow 1,2,*, Susan Makris 1, Cheryl Siegel Scott 1, Stanley S. Barone Jr 1
Article first published online: 29 DEC 2009
DOI: 10.1002/bdrb.20222
Published 2009 Wiley-Liss, Inc. (2010)
Early lifestage exposure and potential developmental susceptibility to tetrachloroethylene. Birth Defects Research Part B: Developmental and Reproductive Toxicology, 89: 50–65. doi: 10.1002/bdrb.20222
Author Information: 1 National Center for Environmental Assessment, Office of Research and Development, US Environmental Protection Agency, Washington, DC. 2 Brookings Institution, Legis Congressional Fellow, Washington, DC
*National Center for Environmental Assessment, Office of Research and Development, US Environmental Protection Agency, Mailcode 8623-P, Washington, DC 20460

Environ Health Perspect. 2006 May; 114(5): 735–739.
Published online 2006 January 13. doi: 10.1289/ehp.8754
PMCID: PMC1459928
Research
Gestational Mercury Vapor Exposure and Diet Contribute to Mercury Accumulation in Neonatal Rats
Daniel L. Morgan, 1, Herman C. Price, 2, Reshan Fernando, 3, Sushmita M. Chanda, 1, Robert W. O’Connor, 2, Stanley S. Barone, Jr., 4, David W. Herr, 4, and Robert P. Beliles 5

1. National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA
   
2. ManTech Environmental Technology Inc., Research Triangle Park, North Carolina, USA
   
3. Research Triangle Institute, Research Triangle Park, North Carolina, USA
   
4. National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA
   
5. U.S. Environmental Protection Agency, Washington, DC, USA Address correspondence to D.L. Morgan, Respiratory Toxicology, Mail Stop IF-00, NIEHS, 101 TW Alexander Dr., P.O. Box 12233, Research Triangle Park, NC 27709 USA. Telephone: (919) 541-2264. Fax: (919) 541-0356.
   The authors declare they have no competing financial interests.

Neurotoxicology. 2006 Sep;27(5):861-74. Epub 2006 Jul 21.
Hershey Medical Center Technical Workshop Report: optimizing the design and interpretation of epidemiologic studies for assessing neurodevelopmental effects from in utero chemical exposure.
Amler RW, Barone S Jr, Belger A, Berlin CM Jr, Cox C, Frank H, Goodman M, Harry J, Hooper SR, Ladda R, LaKind JS, Lipkin PH, Lipsitt LP, Lorber MN, Myers G, Mason AM, Needham LL, Sonawane B, Wachs TD, Yager JW.
School of Public Health, New York Medical College, USA.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1935386/pdf/nihms11719.pdf
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1935386/?tool=pubmed
Free full text 24 pages

Contact: Judy S. LaKind, Ph.D.
LaKind Associates, LLC, 106 Oakdale Avenue ,Catonsville, Maryland USA 21228
PH: 410.788.8639, FX: 410.78.1971

Robert W. Amler, School of Public Health, New York Medical College.

Stanley Barone, Jr., National Center for Environmental Assessment, Office of Research and Development, US Environmental Protection Agency.

Aysenil Belger, Department of Psychiatry, Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill.

Cheston M. Berlin, Jr., Department of Pediatrics, Children’s Hospital, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine.

Christopher Cox, Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University.

Harry Frank, Departments of Psychology and Earth & Resource Sciences, The University of Michigan-Flint.

Michael Goodman, Department of Epidemiology, Emory University Rollins School of Public Health.

Jean Harry, Laboratory of Neurobiology, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services.

Stephen R. Hooper, Clinical Center for the Study of Development and Learning, University of North Carolina School of Medicine.

Roger Ladda, Milton S. Hershey Medical Center, Pennsylvania State University College of Medicine.

Judy S. LaKind, LaKind Associates, LLC, Milton S. Hershey Medical Center, Pennsylvania State College of Medicine, University of Maryland School of Medicine.

Paul H. Lipkin, Division of Neurology and Developmental Medicine, The Kennedy Krieger Institute, The Johns Hopkins University School of Medicine.

Lewis P. Lipsitt, Department of Psychology, Brown University.

Matthew N. Lorber, National Center for Environmental Assessment, Office of Research and Development, US Environmental Protection Agency.

Gary Myers, Division of Pediatric Neurology, University of Rochester Medical Center.

Ann M. Mason, Research Foundation for Health and Environmental Effects.

Larry L. Needham, Division of Environmental Health Laboratory Sciences, Centers for Disease Control and Prevention.

Babasaheb Sonawane, National Center for Environmental Assessment, Office of Research and Development, US Environmental Protection Agency.

Theodore D. Wachs, Department of Psychological Sciences, Purdue University.

Janice W. Yager, Environment Division, Electric Power Research Institute.

"Neurotoxicology. Author manuscript; available in PMC 2007 July 31.
Published in final edited form as: Neurotoxicology. 2006 September; 27(5): 861–874.
Published online 2006 July 21. doi: 10.1016/j.neuro.2006.07.008
PMCID: PMC1935386
NIHMSID: NIHMS11719 Robert W. Amler, Stanley Barone, Jr., Aysenil Belger, Cheston M. Berlin, Jr., Christopher Cox, Harry Frank, Michael Goodman, Jean Harry, Stephen R. Hooper, Roger Ladda, Judy S. LaKind, Paul H. Lipkin, Lewis P. Lipsitt, Matthew N. Lorber, Gary Myers, Ann M. Mason, Larry L. Needham, Babasaheb Sonawane, Theodore D. Wachs, and Janice W. Yager

I. Executive Summary

Neurodevelopmental disabilities affect 3–8% of the four million babies born each year in the U.S. alone, with known etiology for less than 25% of those disabilities.

Numerous investigations have sought to determine the role of environmental exposures in the etiology of a variety of human neurodevelopmental disorders (e.g., learning disabilities, attention deficit-hyperactivity disorder, intellectual disabilities) that are manifested in childhood, adolescence, and young adulthood. A comprehensive critical examination and discussion of the various methodologies commonly used in investigations is needed. The Hershey Medical Center Technical Workshop: Optimizing the Design and Interpretation of Epidemiologic Studies for Assessing Neurodevelopmental Effects from In Utero Chemical Exposure provided such a forum for examining these methodologies. The objective of the Workshop was to develop scientific consensus on the key principles and considerations for optimizing the design and interpretation of epidemiologic studies of in utero exposure to environmental chemicals and subsequent neurodevelopmental effects. (The Panel recognized that the nervous system develops post-natallyand that critical periods of exposure can span several developmental life stages.)

Discussions from the Workshop Panel generated 17 summary points representing key tenets of work in this field. These points stressed the importance of: a well-defined, biologically plausible hypothesis as the foundation of in utero studies for assessing neurodevelopmental outcomes; understanding of the exposure to the environmental chemical(s) of interest, underlying mechanisms of toxicity, and anticipated outcomes; the use of a prospective, longitudinal cohort design that, when possible, runs for periods of two to five years, and possibly even longer, in an effort to assess functions at key developmental epochs; measuring potentially confounding variables at regular, fixed time intervals; including measures of specific cognitive and social-emotional domains along with non-cognitive competence in young children, as well as comprehensive measures of health; consistency of research design protocols across studies (i.e., tests, covariates, and analysis styles) in an effort to improve inter-study comparisons; emphasis on design features that minimize introduction of systematic error at all stages of investigation: participant selection, data collection and analysis, and interpretation of results; these would include (but not be limited to) reducing selection bias, using double-blind designs, and avoiding post-hoc formulation of hypotheses; a priori data analysis strategies tied to hypotheses and the overall research design, particularly for methods used to characterize and address confounders in any neurodevelopmental study; actual quantitative measurements of exposure, even if indirect, rather than methods based on subject recall; careful examination of standard test batteries to ensure that the battery is tailored to the age group as well as what is known about the specific neurotoxic effects on the developing nervous system; establishment of a system for neurodevelopmental surveillance for tracking the outcomes from in utero exposure across early developmental time periods to determine whether central nervous system injuries may be lying silent until developmentally challenged; ongoing exploration of computerized measures that are culturally and linguistically sensitive, and span the age range from birth into the adolescent years; routine incorporation of narrative in manuscripts concerning the possibility of spurious (i.e., false positive and false negative) test results in all research reportage (this can be facilitated by detailed, transparent reporting of design, covariates, and analyses so that others can attempt to replicate the study); forthright, disciplined, and intellectually honest treatment of the extent to which results of any study are conclusive -- that is, how generalizable the results of the study are in terms of the implications for the individual study participants, the community studied, and human health overall; confinement of reporting to the actual research questions, how they were tested, and what the study found, and avoiding, or at least keeping to a minimum, any opinions or speculation concerning public health implications; education of clinicians and policymakers to critically read scientific reports, and to interpret study findings and conclusions appropriately; and recognition by investigators of their ethical duty to report negative as well as positive findings, and the importance of neither minimizing nor exaggerating these findings.

II. Workshop Rationale

Neurodevelopmental disabilities affect 3–8% of 4 million babies born each year in the U.S. alone (Weiss and Landrigan, 2000). Fewer than 25% of these neurodevelopmental disabilities have a known etiology. It is now appreciated that subtle damage that occurs to the nervous system during early development can manifest much later in life. This makes the ability to establish a relationship with events occurring during gestation even more challenging. In an effort to identify the causes of neurodevelopmental disabilities, epidemiologic research is a valuable tool that can be used to identify potential links between disease and genetic and environmental factors. Numerous epidemiologic studies have examined potential links between in utero or early postnatal exposure and specific chemicals (e.g., pharmaceuticals, environmental chemicals such as lead, methylmercury, polychlorinated biphenyls [PCBs]) and adverse developmental or behavioral effects in children (see Rice and Barone, 2000, for a recent review).

These studies have been invaluable in laying the groundwork for how such investigations should be conducted, and provide an excellent foundation for future studies.

Given the current interest in expanding such studies to address issues related to adverse effects of low-level exposures to environmental factors, an examination of the methodologies commonly used would be of significant value to investigators in the design and analysis of future studies.

Such a review would assess the strengths and limitations of methodological approaches used to date, and consider scientific and technical advances in relevant methodologies, such as exposure assessment, neurodevelopmental assessment, interpretation of data, and incorporation of an evidence-based approach to identify health concerns.

This review would serve to identify key methodological factors that ultimately determine the value and strength of a study.

The Hershey Medical Center Technical Workshop: Optimizing the Design and Interpretation of Epidemiologic Studies for Assessing Neurodevelopmental Effects From In Utero Chemical Exposure was a one-day meeting held in conjunction with the 22nd International Neurotoxicology Conference (Environment and Neurodevelopmental Disorders), Research Triangle Park, North Carolina, September 2005.

Within this framework, a multidisciplinary panel was convened to discuss issues as they relate to the design, conduct, interpretation, and dissemination of information of human studies examining the potential adverse effects from gestational exposure to various environmental agents.

The Panel was comprised of experts in psychology, medicine, risk/exposure assessment, analytical chemistry, neuroimaging, epidemiology, toxicology, statistics, psychiatry, pediatrics, pediatric neuropsychology, and neurology.

Each member had experience and interest in assessing the effects of environmental chemical exposure on human development.

This Workshop was organized to discuss the important principles for detecting the effects of environmental exposures on neurobehavioral development and to make recommendations for the design of future studies evaluating the impact of in utero exposures. (The Panel recognized that the nervous system develops post-natally and that critical periods of exposure can span several developmental life stages.)

The discussions were initiated by a series of questions related to scientific methodological issues that were posed to the Panel prior to the Workshop (see Table 1).

Given that adverse effects may emerge after long latent periods, the Panel discussed how effects that manifest as irreversible damage to the central nervous system, progressive neurodegeneration, or subtle neurological dysfunction first appearing in adolescence and adulthood could be considered and incorporated into study designs.

The Panel focused on identifying ‘best practices’ for such studies which often required revisiting the basic principles underlying current epidemiological studies.

The Panel did not evaluate conclusions or findings from previous neurodevelopmental epidemiological studies related to the topic of environmental exposure; however, discussion of focal points from such studies served the basis for identifying critical points for consideration in any future study designs.

The outcome of this Workshop serves to provide input for both the design of future investigations and establishment of standards whereby one can judge the adequacy of reported studies.

This report represents a summary of the Panel deliberations, including current basic scientific tenets that have been embraced by this field, as well as considerations for future work.....methanol from aspartame, wood and cigarette smoke, some fresh coffees, and many sources is made by ADH1 enzyme into formaldehyde within human blood vessels and cells, creating many modern diseases, the WC Monte paradigm: Rich Murray 2012.06.02

See his two 1-hour video lectures May 2012
http://www.WhileScienceSleeps.com

The 200 mg aspartame in a 12-oz can of aspartame drink is 11% by weight methanol, 22 mg, which is soon released from the GI tract into the blood, where quickly any tissues with high levels of the ADH1 enzyme within the cells of blood capillary walls and adjacent tissues, especially liver, kidney, brain, retina, etc., in humans only, turn the methanol into formaldehyde within these cells, which, being highly reactive, quickly binds with and disables DNA, RNA, and proteins inside the cells, causing cell death, attracting macrophages (white blood cells), which also die, creating durable, cumulative, evolving complex micro lesions.

This affects the fetus, as well, or not so well...So, there are many resulting novel modern "diseases of civilization" in humans only, for each type of damaged tissue, including Alzheimer's, multiple sclerosis, lupus, arthritis, the birth defects spina bifida, autism, and Asperger's, many specific cancers, and chronic ailments of liver, kidney, heart, lung, joint, skin, muscle, etc.

Other methanol/formaldehyde sources include wood, peat and cigarette smoke, some fresh coffees, fermented and smoked foods, fruits juices vegetables heated in sealed jars and cans, some dark wines and liquors, bacteria in the colon, genetic flaws in metabolism, vehicle fumes, leaky fossil fuel stoves and heaters, processed wood products of all kinds, mobile homes, old Ditto type purple ink mimeograph duplicating machines in schools and offices, chemical biology autopsy mortuary facilities, heated wood in particleboard, pressed wood and paper factories, and many personal care cleaners and products...

The Monte methanol/formaldehyde toxicity paradigm MMFTP is backed by 740 references, given free online as full pdf texts by Prof. (retired 2004, Arizona State University, Nutrition and Food Sciences) Woodrow C. Monte, http://www.WhileScienceSleeps.com, along with his 2012 January 240 page text "While Science Sleeps", with two free chapters on "Autism and Other Birth Defects", and "Multiple Sclerosis", and free full earlier articles and references on MMFTP.

Methanol/formaldehyde paradigm for multiple sclerosis, free full 56 page chapter 9 pdf, While Science Sleeps, 146 full text references online, Prof. Woodrow C. Monte: Rich Murray 2012.03.20
http://rmforall.blogspot.com/2012/03/methanolformaldehyde-paradigm-for.html
http://health.groups.yahoo.com/group/aspartameNM/message/1642

Methyl alcohol ingestion as a model etiologic agent in multiple sclerosis, WC Monte, D Glanzman, C Johnston; Methanol induced neuropathology in the mammalian central nervous system, Woodrow C. Monte, Renee Ann Zeising, both reports 1989.12.04: Murray 2007.12.28 2012.05.01
http://rmforall.blogspot.com/2012/05/methyl-alcohol-ingestion-as-model.html
http://health.groups.yahoo.com/group/aspartameNM/message/1646
Posted again Tuesday, May 1, 2012

http://rmforall.blogspot.com/2007/12/methyl-alcohol-ingestion-as-model.html
http://health.groups.yahoo.com/group/aspartameNM/message/1499
Friday, December 28 2007

Rich Murray
MA Boston University Graduate School 1967 psychology,
BS MIT 1964 history and physics,
Rich Murray
254-A Donax Avenue, Imperial Beach, CA 91932-1918
rmforall@gmail.com
505-819-7388 cell
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