The Honorable John Shimkus

Mr. Cook, you testified that the regulatory level for barium is an

arbitrary value, set in a time when there were no toxicology studies.

Is it your opinion that there are other substances that are regulated

using evaluations based on outdated or incomplete science?

Yes, I am of the strong opinion that a substantial number of other

substances are also being regulated based upon bad science. In fulfilling

Chemical Products Corporation's product stewardship obligations, I have

found over-regulation based on bad science for both of the materials I

have investigated. Not only have I encountered a resolute disregard for

sound science at IRIS and failure by EPA to relax regulatory levels for

barium consistent with sound science, but I have also encountered

egregious scientific misconduct at the National Toxicology Program to

support bad science concerning another of our products, Anthraquinone.

I believe that it is beyond the realm of possibility that only the two

substances I have evaluated are being over-regulated to the detriment of

U.S. manufacturers.

 Anthraquinone, another of Chemical Products Corporation's

products, is a useful and benign industrial chemical. In the early-1990s,

NTP obtained an Anthraquinone sample for animal testing which was

contaminated with a potent mutagen. NTP did not become aware of this

contamination until years after animal testing had been completed.

Anthraquinone is not a mutagen; this fact was only acknowledged by NTP

as a result of a Request for Correction and a subsequent Request for

Reconsideration I submitted in 2003 under the Information Quality Act. In

December 2004, highly significant false information was presented to peer

reviewers to finally gain approval of the conclusions advocated by NTP

staff. In 2006, NTP staff fabricated a document to support NTP's rejection

Page 1 of 5 
of my Request for Correction of the final Technical Report 494. 

Anthraquinone has been an important raw material for the production

of textile dyes for more than a century; more recently it has also found a

use in the U.S. paper industry as a catalyst to increase pulp yields and

thereby decrease energy usage and paper production costs.

Anthraquinone has not been manufactured in the U.S. since the early

1980's; Chemical Products Corporation purchases imported

Anthraquinone as a dry powder and formulates it into a stable slurry that

our paper industry customers can easily store and pump into their

papermaking processes. 

NTP incorrectly declared that Anthraquinone was a mutagen, based

upon its own positive mutagenicity assay of a single contaminated

sample, when it published the results of its animal studies in 1999. Even

though several earlier published studies had reported that Anthraquinone

is not mutagenic, NTP chose to dismiss those studies without

investigating the issue. NTP reported in 1999 that it had found clear

evidence that Anthraquinone caused cancer in rats and mice. 

When NTP's startling assertions were published for public review

and comment in early 1999, I investigated further and found that a

specific potent mutagenic contaminant had been identified in some

Anthraquinone samples. This information was contained in the

International Uniform Chemical Information Database and also in EPA's

TSCA file for Anthraquinone. The identified mutagenic contaminant came

from an obsolete manufacturing process which is no longer practiced

anywhere in the world. I obtained a sample of NTP's test material and

had it analyzed in late 1999; I found this same potent mutagen in NTP's

test material. NTP had unwittingly obtained contaminated test material

produced by an obsolete, dirty manufacturing process; no commercial

Anthraquinone anywhere in the world has been contaminated with this

Page 2 of 5 
potent mutagen for nearly two decades. I immediately informed NTP of

my findings. NTP took no action to correct its technical report for more

than three years after it was informed that it had tested a contaminated

Anthraquinone material. 

When the Information Quality Act came into effect in late 2002, I

immediately submitted a Request for Correction which was promptly

denied by NTP. I then submitted a Request for Reconsideration in 2003;

it was adjudicated by the Deputy Director of the National Institute of

Environmental Health Sciences. He concluded that the mutagenic

contamination in the Anthraquinone sample tested by NTP made it

impossible to be certain what had caused the cancers in the test animals;

he withdrew NTP's 1999 Technical Report 494 on Anthraquinone in

September 2003. 

In 2004 NTP staff issued a revised technical report which

acknowledged that Anthraquinone is not a mutagen and that a mutagenic

contaminant had been found in the material that NTP had fed to rats and

mice. However, NTP still insisted that its test results proved that

Anthraquinone was solely responsible for the cancers found in rats and

mice. The revised technical report was peer reviewed first in February

2004 and then reopened for additional peer review in December of 2004. 

In December 2004, NTP's present Associate Director orchestrated

the removal of the restrictions placed in Technical Report 494 by the

February 2004 peer review panel. “New” highly significant false

information was presented to the peer review panel in December without

the requisite prior publication for public review and comment. This false

information was incorporated into the final technical report along with the

same conclusions that had been in the 1999 technical report – those

conclusions allowed NTP staff to proceed with publication of a paper

characterizing Anthraquinone as a carcinogen in March 2005.

Page 3 of 5 
NTP Technical Report 494 on Anthraquinone was published in

September 2005. California's Proposition 65 statute requires that any

chemical identified as a carcinogen in a NTP technical report be added to

the Proposition 65 list under the “Authoritative Bodies Mechanism”. Thus,

U.S. papermakers have been faced with the dilemma of weighing the

energy and cost savings achieved by using Anthraquinone in their pulping

process against the risk that their myriad paper products entering

California might be challenged under the Proposition 65 regulation. We

feel certain that sales of our Anthraquinone product have been adversely

impacted by the bad science contained in NTP Technical Report 494.

Multiple Freedom of Information Act requests and a Freedom of

Information Act appeal have permitted me to compile documentary

evidence demonstrating that the new information presented to the

December 2004 peer review panel and incorporated into the published

NTP Technical Report 494 is false.

By May 2006 I had determined that Technical Report 494 was fatally

flawed; I submitted a Request for Correction under the Information Quality

Act seeking its withdrawal. My Request was denied by NTP. I then

submitted a Request for Reconsideration at the end of 2006; my

submission included additional documents demonstrating conclusively

that Technical Report 494 contains highly significant false information.

My submission was adjudicated by the Director of the Office of Science

Policy at the National Institute of Environmental Health Sciences. After

an 18 month delay, my Request for Reconsideration was denied on

September 22, 2008; the documentation I submitted had been ignored. 

I turned to the Office of Research Integrity for help and discovered

that ORI does not concern itself with evidence of scientific misconduct at

NTP. Director John E. Dahlberg of the Division of Investigative Oversight

stated in a letter to me dated January 16, 2009, “I also note that ORI does

Page 4 of 5 
not have authority to conduct the investigation you request. Our role is

limited by departmental policy to conducting oversight review of

investigations conducted by the institutions where the alleged misconduct

took place.” Thus, as long as NTP does not enforce scientific integrity by

investigating alleged misconduct by its staff, ORI will not concern itself

with scientific misconduct at NTP. NIEHS and NTP Director Linda S.

Birnbaum has refused to investigate. 

I have twice nominated Anthraquinone to NTP's Office of Chemical

Nomination and Selection in an effort to obtain a valid scientific study to

replace NTP's egregiously flawed existing technical report. These letters

are attached as an appendix. I respectfully request this Subcommittee's

assistance in obtaining a valid scientific evaluation of Anthraquinone to

correct NTP Technical Report 494. Safeguards would certainly need to be

put into place at NTP to insure the scientific validity of a new study

conducted there.

In summary, I cannot imagine that I happened to stumble upon the

only two instances of needlessly burdensome regulation based on bad

science. I feel quite certain that many companies in many different

industries in the United States are suffering under unnecessary regulatory

burdens based upon the same indifference to sound science and lack of

scientific integrity.

APPENDIX

Two letters submitted to NTP's Office of Chemical Nomination and

Selection nominating Anthraquinone for a valid scientific study to replace

NTP Technical Report 494

Each letter is 7 pages – a total of 14 pages appended.

Page 5 of 5 
December 5, 2008

Office of Chemical Nomination and Selection

National Toxicology Program/NIEHS

MD EC-31

P.O. Box 12233

Research Triangle Park, NC 27709

Subject: Nomination of Anthraquinone, CAS # 84-65-1,

for study - Replacement of scientifically

untenable NTP Technical Report 494

Dear Sir or Madam:

The National Toxicology Program has demonstrated

a strong interest in naturally occurring quinones

containing the anthraquinone ring, as a class.

Anthraquinone, CAS #84-6-1, also known as 9,10-

anthraquinone or 9,10-dioxoanthracene, is the parent

compound of this class.

Unfortunately, animal studies conducted by NTP in

the mid-1990s employed an Anthraquinone test article

contaminated with mutagenic 9-nitroanthracene

(anthraquinone is not a mutagen). Uncorrected

scientific misconduct on the part of individuals within

NTP has resulted in publication of scientifically

Chemical

Products

Corporation

102 Old Mill Road , S.E.E

P.O. Box 2470

Cartersville, Georgia

30120-1692

Phone: 770-382-2144

Fax: 770-386-6053

e-mail: jcook@cpc-us.com
 Page 2 December 5, 2008

untenable conclusions regarding the carcinogenic activity of

Anthraquinone in NTP Technical Report 494 (TR494) 1. Innes

et al. (1969)2found no carcinogenic activity for

Anthraquinone in mice, and Huff et al. (1996)3 predicted that

Anthraquinone would not be carcinogenic based upon

structural characteristics of its primary metabolite, 2-

hydroxyanthraquinone; the test article employed in the

TR494 studies was so contaminated as to confound the

interpretation of the results of those studies.

The carcinogenic potential of anthraquinone was

evaluated by Innes et al. (1969) in two strains of mice. At 7

days of age and continuing through 28 days of age, groups of

18 male or 18 female B6C3F1 or B6AKRF1 mice received 464

mg anthraquinone/kg body weight daily by gavage. After 28

days, these groups received 1,206 ppm anthraquinone in feed

for 18 months. No increase in tumors in either strain of mice

was associated with administration of anthraquinone.

1 Toxicology and Carcinogenesis Studies of Anthraquinone

(CAS No. 84-65-1) In F344/N Rats and B6C3F1 Mice (Feed

Studies); National Toxicology Program Technical Report 494;

NIH publication 05-3953.

2 Innes, J.R.M., Ulland, B.M., Valerio, M.G., Petrucelli, L.,

Fishbein, L., Hart, E.R., Pallotta, A.J., Bates, R.R., Falk, H.L.,

Gart, J.J., Klein, M., Mitchell, I., and Peters, J. (1969).

Bioassay of pesticides and industrial chemicals for

tumorigenicity in mice: A preliminary note. J. Natl. Cancer

Inst. 42, 1101-1114.

3 Huff, James; Weisburger, Elizabeth; and Fung, Victor A.;

“Multicomponent Criteria for Predicting Carcinogenicity:

Dataset of 30 NTP Chemicals”; Environmental Health

Perspectives Supplements Volume 104; Number S5; October

1996.
 Page 3 December 5, 2008

Huff et al. (1996) predicted that Anthraquinone would

not be carcinogenic based upon multicomponent criteria for

predicting carcinogenicity, including structural

considerations of Anthraquinone's primary metabolite, 2-

hydroxyanthraquinone.

In the mid-1990s NTP conducted animal tests using an

Anthraquinone test article manufactured by the nitric acid

oxidation of anthracene which was contaminated with

mutagenic 9-nitroanthracene (Anthraquinone is not a

mutagen). A 1999 TR494, which incorrectly declared the test

substance, Anthraquinone, to be a mutagen, and concluded

that there was clear evidence of carcinogenic activity in both

male and female mice, was withdrawn in September 2003

because it failed to recognize the mutagenic contamination in

the non-mutagenic test article4.

A substantially revised February 2004 TR494 contained

the same conclusions as the withdrawn 1999 report, but

included new information that (1) “pure” anthraquinone is

not mutagenic, (2) the TR494 test article was contaminated

with mutagenic 9-nitroanthracene, (3) the TR494 test article

had been found to be mutagenic to Salmonella typhimurium

strains TA98 and TA100 without metabolic activation5, and

4 HHS Information Quality Web Site. Information Requests

for Corrections and HHS' Responses. Item 5. 2003.

http://aspe.hhs.gov/infoQuality/requests.shtml

5 Butterworth, B.E., Mathre, O.B., and Ballinger, K.; “The

preparation of anthraquinone used in the National Toxicology

Program cancer bioassay was contaminated with the mutagen

9-nitroanthracene”; Mutagenesis 16, 169-177; 2001.
 Page 4 December 5, 2008

(4) the primary anthraquinone metabolite, 2-

hydroxyanthraquinone, had been found by NTP to be

mutagenic to TA98 without S9 activation in a 2003

preincubation mutagenicity assay, thus, being cited as the

mutagen potentially responsible for the observed tumors.

NTP concealed an earlier negative preincubation assay for 2-

hydroxyanthraquinone67in conflict with its finding.

Nevertheless, on February 18, 2004 the NTP's Technical

Reports Review Subcommittee restricted the conclusions in

TR494 to “anthracene-derived anthraquinone”, in reference

to the obsolete TR494 test article production method which

contributed mutagenic contaminants. No anthracene-derived

Anthraquinone has been available commercially within the

U.S. for many years.

In an unprecedented action, NTP commissioned further

mutagenicity testing in the summer of 2004 after the

February 2004 peer review. To remove the “anthracenederived anthraquinone” restriction from the conclusions

presented in the final TR494, NTP presented a new negative

mutagenicity assay conducted in the summer of 2004 to

NTP's December 9, 2004 Technical Reports Review

6 Tikkanen, L.; Matsushima, T.; Natori, S.; “Mutagenicity of

anthraquinones in the Salmonella preincubation test”;

Mutation Research; 116(3-4):297-304; March 1983. This

paper also presents a negative assay for Anthraquinone

which NTP ignored in 1999, but later had to accept as

accurate.

7 Page 91 in TR494 states specifically that Tikkanen et al.

(1983) did not perform testing without S9; in fact, negative

preincubation assays in strains TA98, TA100 and TA 2637

were reported without S9 activation.
 Page 5 December 5, 2008

Subcommittee for “Sample A07496”as a conclusive

demonstration that the TR494 test article, “Anthraquinone,

Lot 5893”, had not been mutagenic after all. False

information was provided to the peer review panel to

overcome a concern expressed by one of the reviewers that

mutagenic impurities might have decomposed during the

more than 7 years which had elapsed since the conclusion of

the animal studies8. This new information was incorporated

into the final TR494 and the “anthracene-derived

anthraquinone” limitation on the conclusions was removed.

Investigation has revealed that “Sample A07496” has

been falsely presented as being an aliquot of the TR494 test

article “Anthraquinone Lot 5893”. The Test Article Receipt

and Transfer Report from BioReliance Testing Laboratories

(BTL), the laboratory which performed the 2004 mutagenicity

assay for NTP, shows that “Sample A07496” was not labeled

“Anthraquinone, Lot 5893”, the TR494 test article, when it

was received by BTL and assigned sample number A074969.

In a remarkable perpetuation of scientific misconduct,

NIEHS's September 22, 2008 Information Quality response

confirmed that any aliquot of the TR494 test article would be

labeled “Anthraquinone, Lot 5893” when shipped from the

8 HHS Information Quality Web Site. Information Requests

for Corrections and HHS' Responses. Item 28 at section c.

http://aspe.hhs.gov/infoQuality/requests.shtml

9 BioReliance Testing Laboratories Test Article Receipt and

Transfer Reports; Documents Responsive to NIH FOI No.

33011; 7 pages; attachment to item c2. at Item 28 in

http://aspe.hhs.gov/infoQuality/requests.shtml
 Page 6 December 5, 2008

Battelle Columbus Laboratories test article repository, but

ignored the BTL Test Article Receipt and Transfer Report

submitted to document the fact that “Sample A07496” was

not so labeled when it was received by BTL for mutagenicity

assay10 . Enforcement of the HHS Information Quality

Guidelines appears to be moribund; NIEHS is currently

turning a blind eye to scientific misconduct within its own

ranks.

Scientific misconduct on the part of NTP staff resulted

in the existing NTP Technical Report 494 (TR494) being

approved at its third peer review on December 9, 2004.

Accepted scientific and ethical standards have not been

enforced within NTP, as demonstrated by NIH's September

22, 2008 Information Quality response regarding deficiencies

in TR494 as described above. Materially false information

remains an integral part of TR494, and the accuracy of the

prediction by Huff et al. (1996) that anthraquinone is not a

carcinogen has yet to be tested in a scientifically-sound

study.

We respectfully submit that the February 18, 2004 NTP

Technical Reports Review Subcommittee was correct in its de

facto determination that mutagenic impurities confounded

the results of the TR494 animal studies (hence, the

restriction of the conclusions presented to only “anthracenederived anthraquinone”). We nominate Anthraquinone, CAS

10 HHS Information Quality Web Site. Information Requests

for Corrections and HHS' Responses. Item 28 at section c.

http://aspe.hhs.gov/infoQuality/requests.shtml
 Page 7 December 5, 2008

# 84-65-1, produced by either of the dominant present

industrial manufacturing processes – the Friedel-Crafts

process or the Diels-Alder process - for study to obtain a

scientifically-sound determination of the carcinogenic

potential of anthraquinone containing only biologically

innocuous impurities.

Chemical Products Corporation markets Anthraquinone

to the pulp and paper industry.

Sincerely,

Jerry A. Cook

Technical Director
November 24, 2009

Office of Chemical Nomination and Selection

National Toxicology Program/NIEHS

MD EC-31

P.O. Box 12233

Research Triangle Park , NC 27709

Subject:

Nomination of Anthraquinone, CAS # 84-65-1,

for long-term bioassay – NTP Technical Report

494 has been recognized as deficient

Dear Sir or Madam:

The international scientific community has

recognized that NTP Technical Report 494 does not

represent sound science. Professor Alan R. Boobis et

al. state in the October 2009 issue of Toxicologic

Pathology, “The data for anthraquinone are

considered suspect because other

carcinogenicity studies were negative, and the

NTP carcinogenicity study used a batch of

Chemical

Products

Corporation

102 Old Mill Road SE

P.O. Box 2470

Cartersville, Georgia

30120-1692

Phone: 770-382-2144

Fax: 770-386-6053

e-mail: jcook@cpc-us.com
Nomination of Anthraquinone for study to correct Technical Report 494

Page 2 November 25, 2009

anthraquinone contaminated with the potent

mutagen 9-nitroanthracene at a level of 1,200

ppm (Butterworth, Mathre, and Ballinger 2001).

(A purified sample was negative in the Ames

test.) Certainly, it can be said that the material

used by the NTP was mutagenic...” (“A DataBased Assessment of Alternative Strategies for

Identification of Potential Human Cancer Hazards”;

Alan R. Boobis, Samuel M. Cohen, Nancy G. Doerrer,

Sheila M. Galloway, Patrick J. Haley, Gordon C. Hard,

Frederick G. Hess, James S. Macdonald, Stéphane

Thibault, Douglas C. Wolf and Jayne Wright; Toxicol

Pathol; 37; 714-732; 2009 - at page 719).

The deficient NTP carcinogenicity study

referenced by Professor Boobis et al. is reported in

NTP Technical Report 494 (TR494); this report

contains a negative mutagenicity assay falsely

attributed to the contaminated NTP test material.

This false assay was presented as “new information”

at the third peer review of this technical report on

December 9, 2004 and resulted in acceptance of

scientifically untenable conclusions by the Technical

Reports Review Subcommittee on that date.

Documentary evidence (obtained through a Freedom
Nomination of Anthraquinone for study to correct Technical Report 494

Page 3 November 25, 2009

of Information Act appeal) of misconduct on the part

of NTP scientists Dr. Richard Irwin, Dr. Cynthia Smith,

and Dr. John Bucher was willfully ignored by Dr. Joyce

Martin when she denied Chemical Products

Corporation's Request for Reconsideration under the

DHHS Information Quality Guidelines in September

2008.

Rigorous scientific analysis led Professor Boobis

et al. to conclude, “Certainly, it can be said that

the material used by the NTP was mutagenic”,

based on knowledge of the potency of the 9-

nitroanthracene contaminant. Professor Boobis at

Imperial College London has published over 200

original research papers and is an Editor-in-Chief of

Food and Chemical Toxicology. He was deputy

chairman of the U.K. Advisory Committee on

Pesticides (1999-2002) and is a member of a number

of national and international grant review and

advisory committees, including the UK Committees

on Carcinogenicity and on Toxicity. He was awarded

the Order of the British Empire for his work on the

risk assessment of pesticides in 2003. He is an

Honorary Member of EUROTOX, a Fellow of the British

Toxicology Society, and a Fellow of the Institute of
Nomination of Anthraquinone for study to correct Technical Report 494

Page 4 November 25, 2009

Biology. Fortunately, a commitment to research

integrity and correction of the scientific record exists

within the international scientific community.

Professor Boobis et al. have provided an

essential correction of the scientific record regarding

Anthraquinone. The REACH Substance Information

Exchange Forum (SIEF), of which I am a member, will

disregard the conclusions presented in TR494 when

preparing the REACH registraion dossier for

anthraquinone on the basis that they are

scientifically untenable. The European Chemicals

Agency has been formally requested by the REACH

SIEF to confirm the SIEF's determination that TR494

does not represent sound science.

The final TR494, published in September 2005,

also misrepresents the scientific record concerning

the mutagenicity of anthraquinone's primary

metabolite, 2-hydroxyanthraquinone. After the 1999

TR494 had been withdrawn because “the presence

of this contaminant [9-nitroanthracene] raises

doubt as to the effect(s) of anthraquinone

itself, or its metabolites, and confounds

interpretation of the NTP studies...” (NIEHS
Nomination of Anthraquinone for study to correct Technical Report 494

Page 5 November 25, 2009

Deputy Director Samuel H. Wilson's determination in

September 2003), NTP conducted a mutagenicity

assay of 2-hydroxyanthraquinone which purported to

show that it was mutagenic to Salmonella

typhimurium TA98 without metabolic activation. Thus,

Dr. Irwin at al. presented 2-hydroxyanthraquinone as

a direct acting mutagen produced in situ which could

be responsible for the carcinogenicity observed in the

TR494 studies through a mechanism involving

mutagenicity. A conflicting earlier negative

preincubation assay of 2-hydroxyanthraquinone in

TA98 without metabolic activation was withheld from

peer reviewers and its existence is specifically denied

in TR494; at page 91, TR494 incorrectly states that

Tikkanen et al. (1983) did not perform mutagenicity

assays in the absence of S9 metabolic activation; in

fact, Tikkanen et al. (1983) reported negative assays

of 2-hydroxyanthraquinone in 3 strains - TA98, TA100

and TA 2637 – in the absence of S9 metabolic

activation (Tikkanen, L.; Matsushima, T.; Natori, S.;

Mutagenicity of anthraquinones in the Salmonella

preincubation test; Mutation Research; 116(3-4):297-

304; March 1983).
Nomination of Anthraquinone for study to correct Technical Report 494

Page 6 November 25, 2009

An additional negative assay of 2-

hydroxyanthraquinone in TA98 without metabolic

activation was reported by Butterworth et al. in

August 2004 (Butterworth, B.E., Mathre, O.B., and

Ballinger, K.E., Adalsteinsson, O.; Contamination is a

Frequent Confounding Factor in Toxicology Studies

with Anthraquinone and Related Compounds; Int J

Toxicol; 23; No. 5; 335-344; 2004).

In summary, Anthraquinone is not a mutagen,

but the test article employed in the studies

conducted by NTP in the mid-1990s contained

biologically significant mutagenic contamination – it

was found to be mutagenic to Salmonella

typhimurium strains TA98 and TA100 without S9

metabolic activation (less so with metabolic

activation). Misconduct on the part of NTP scientists

resulted in publication of a final technical report

which contains a false negative mutagenicity for the

TR494 test article and misrepresents the scientific

record concerning the mutagenicity of the primary

anthraquinone metabolite, 2-hydroxyanthraquinone.

The international scientific community has

recognized that the conclusions presented in TR494

are scientifically untenable.
Nomination of Anthraquinone for study to correct Technical Report 494

Page 7 November 25, 2009

We reiterate our nomination of anthraquinone,

CAS # 84-65-1, for long-term bioassay by NTP. The

failure of NIEHS to withdraw TR494 after being

presented conclusive documentation that it is

scientifically deficient demonstrates that NIEHS and

NTP lack a functioning mechanism to insure research

integrity. Thus, a repeated anthraquinone study

should be overseen by an impartial scientific body

outside of NIEHS.

Anthraquinone, CAS #84-65-1, should be chosen

by NTP's Board of Scientific Counselors for study in

2010 for the same reasons that it was chosen by NTP

for study in the early 1990s.

Sincerely,

Jerry A. Cook

Technical Director