EPA Memo: Malathion is A Carcinogen

Dr. Brian Dementi, has a conscience, and as the toxicologist at EPA cannot allow them to continue to poison the people of this country and protect the chemical companies.

Subject:    EPA Internal Memo: Malathion A Carcinogen
Date:       Fri, 23 Jun 2000 18:08:00 -0400
From:        Stephen Tvedten <steve@getipm.com>
Organization:     Get Set Inc. (www.getipm.com)

To:     Lyndon Hawkins <hawkins@empm.cdpr.ca.gov>
          Senior Research Scientist
          State of California, Department of Pesticide Regulation - Integrated Pest Management

Dear Lyndon, I thought you might like to see an internal EPA Memo that Joyce Shepard sent me entitled: EPA Internal Memo: Malathion A Carcinogen.

Dr. Brian Dementi, has a conscience, and as the toxicologist at EPA cannot allow them to continue to poison the people of this country and protect the chemical companies. This internal memo only validates our concerns and the necessity for our meeting with the EPA in Washington on June 28. We have insisted that Dr. Dementi be present. Dr. Dementi knew nothing of the meeting. He does now.

It is unfortunate that Congressman Gary Ackerman has refused to attend this meeting or send a representative because I said we were going to question and challenge Al Gore's environmental concern and input. After all, he is Carole Browner's Mentor and has to know of these findings. Elizabeth Shanklin is presently at the Green Party's Convention in Denver and will be reaching out to Ralph Nader to invite him to our meeting in order for this cover up to be uncovered. There are other Congressional representatives who are interested in joining us as well and other groups are talking with them.

As I have said before, the time has come for us to clean up EPA and Dr. Dementi is the key. He has complained about not being included in the meetings with Cheminova, the manufacturer of malathion. I think this is only the tip of the iceberg. I think pyrethroids are next and we must band together to be effective. Joyce Shepard

On January 27, I submitted to you a memorandum on the indicated subject. This required all of my time since we agreed to perform the task by January 28. I confirm this to be a complicated task. To prepare the January 27 letter it was necessary that I read all of my memoranda and CARC draft reports in order to identify issues and then collate the same in the form of the letter provided. Once engaged in this task, and then realizing it was too ambitious, I discussed the matter with Dwight Welch and Bill Hirzy suggesting we give you a call to say if pursued the project may compromise that which I have already accomplished.

We agreed to strive to fulfill the commitment, to state the issues and identify the various documents wherein the topics were discussed. It is my opinion that the differences of opinion you would have me identify (i.e. "I think x"; "the committee thinks y") are to be found within the documents as cited for each topic. However, toward assisting you further, I have added language to items rendered in II B of my January 27 letter that will set forth my fundamental differences of opinion with respect to those of the committee on those issues.

In seeking to thus help HED, please understand my uneasiness in attempting to embrace or craft into very short sentences that which is developed in much background information.

Persons interested in these subjects must examine the cited documents for factual information and the rationale.

a) positive liver tumorigenic response across all doses, i.e. no NOEL for males, and positive at the top two doses in females.

The finding extending to the lowest dose in males, not unlike the liver tumorigenic response in the female rat in this respect, should be regarded as of particular concern;

b) CARC should not leave unexplained the more remarkable liver tumorigenic responses, particularly in females, in the more recent study, versus findings in the earlier NCI study which the new study was designed to replicate at the top two doses.

2) Thyroid c-cell tumorigenic response in the rat: the finding is positive among male rats across the 0-500 ppm dose range, and cannot be discounted as CARC has done by findings at higher "excessive" doses, lest the study be considered unacceptable for evaluation of this tumorigenic response. Findings at low doses should be of particular concern and discounted only by the most persuasive forms of evidence.

3) Thyroid follicular cell tumors: competing toxicity and increased mortality among male rats at 6000 ppm and 12000 ppm (dose levels considered as excessive by CARC) may have dampened or compromised full expression of a tumorigenic response at these higher doses already evident in the existing data set, i.e. a positive dose trend (p = 0.035) and a nearly positive (p = 0.077) pairwise comparison for the 6000 ppm dose group. I challenge, therefore, CARC's conclusion that the study can be accepted as a negative study for this tumorigenic response. In my view (not stated as such previously, though evident in the reasoning) this tumorigenic response should be viewed as suggestive evidence of carcinogenicity that cannot be discounted because of the unacceptability of the study in male rats at the high dose levels, which CARC itself has called excessive. This is a difficult interpretation which I feel merits an external review.

4) Interpretation of evidence of leukemia in the rat under OSTP (1985)'s definition of carcinogen: evidence of a dose related increased incidence of mortality attributed to leukemia among male rats diagnosed with leukemia constitutes positive evidence of carcinogenicity under the second aspect of OSTP's definition of carcinogen, namely, ".....or significantly decreases the time it takes a naturally occurring(spontaneous) tumor to develop relative to an appropriate background or control group. Either phenomenon is said to represent the effects of a carcinogen." (pp. 10410-10415). I contend the dose-related increased mortality (where mortality itself indicates a more advanced stage) is evidence of a dose-related increased rate of development of leukemia. It could be argued that rats harboring leukemia are simply more susceptible to early death due to the increasing secondary toxicologic burden of the test material, but to confirm that possibility and to discount the possibility of a direct compound effect in development of the response, the mechanism would need to be established. I am not aware CARC has provided a rational response to this issue.

5) Interstitial cell testicular tumor response in the rat: Statistical treatment of this tumorigenic response was positive across all four doses as presented in the study report, and was positive across the top three doses as analyzed by the Peto test within HED. I accept these assessments as showing a dosing related higher incidence than expected of this tumorigenic response, and hence, as a positive carcinogenic effect by recognized definitions of a carcinogen. In my view the Peto test, as required by the CARC, was conducted in the prescribed manner by HED's statistician, and was positive. I am not satisfied with CARC's rationale (absent mechanistic data) for discounting this response, and would desire another expert opinion.

6) Interpretation of rat nasal tissue histopathology and tumorigenic response in the rat: I accept as evidence of carcinogenicity all four extremely rare nasal tumors, two in males and two in females, at the top two dose levels. CARC discounts the findings in males, as I understand, because dosing was excessive, but again, as with certain other tumor types, to the extent tumorigenic findings are discounted in high dose groups, the study in my view is unacceptable in males. The issue is complicated by evidence of nasal histopathology in the long term combined chronic toxicity/carcinogenicity studies in the F344 rat for both malathion and malaoxon, and in the dose range-finding and subchronic inhalation studies of malathion in the rat. While a new inhalation study is being required, I am not satisfied that CARC has an adequate interim handle on risks posed with respect to the nasal mucosa, particularly by the inhalation route of exposure. Nasal tissue vulnerability is an important and unresolved issue at this time.

7) Adequacy of oral cavity assessment for tumorigenic response, and CARC's conclusion regarding squamous cell tumorigenic response: I contend the four extremely rare squamous cell tumors (three in females, one in males) appearing in oral mucosal tissues in the malathion combined chronic toxicity/carcinogenicity study in the rat cannot be discounted as evidence of carcinogenicity. Furthermore, as these tumors were identified in but a partial and inadequate assessment of oral cavity histopathology, there is a greater encumbancy to accept these as real until an adequate histopathology assessment of the entire oral cavity tissues has been performed. I have suggested this need for additional histopathology to CARC, and am concerned the REGISTRANT did not of his own volition follow-up with a complete oral cavity histopathology assessment once these tumors were found. CARC discounted the oral tumors at one meeting on the grounds these tumors are not as rare as the nasal tumors. However, subsequent follow-up information, in my opinion, demonstrates the squamous cell tumors to be essentially as rare as the nasal tissues in various data bases. Am not aware CARC has responded to the more recent information. I have not been availed of the latest, or final, CARC report.

8) Concerted evidence of tumorigenicity (several end points) in low dose groups. For example, are the low dose hepatocellular tumorigenic response in the mouse and rat mutually supportive? I have expressed concern over certain tumorigenic responses that appear to extend into the low dose range, incorporating in certain cases even the lowest dose, absent a NOEL (e.g. male mouse liver tumors, female rat liver tumors, leukemia in male rats as defined above, extremely rare oral squamous cell tumors, possibly testicular tumors). My concern is whether collectively these speak more strongly of a low dose biological effect, than any standing alone, and whether CARC has adequately addressed this possibility in its assessment.

9) Decisions to discount dose levels as excessive for carcinogenicity assessment based on cholinesterase inhibition. Inherent in such review would be the precedent for the decision, existence of guidelines, which forms of the enzyme must be inhibited and by how much, and so on: I do not accept the view that cholinesterase inhibition (absent any guidelines or rationale) alone, absent cholinergic clinical signs, can be cited as adequate rationale to discount a dose level in question as excessive, and in so doing discount remarkable tumorigenic findings observed at that dose level. In my view, inadequate rationale has been provided by CARC to justify dismissal of dose levels as excessive, and in so doing precluding testing at high doses (MTD) called for in cancer bioassays.

10) Acceptability of OSTP's (1985) definition of carcinogen, and if considered acceptable, the rigor of its application in CARC's interpretation of the malathion studies: The OSTP (White House Office of Science and Technology Policy) definition reads as follows: "A chemical carcinogen may be a substance which either significantly increases the incidence of cancer in animals or humans or significantly decreases the time it takes a naturally occurring (spontaneous) tumor to develop relative to an appropriate background or control group. Either phenomenon is said to represent the effects of a carcinogen." (pp.10414-10415) I have sought from CARC its views as to the veracity of this definition of a carcinogen, but my question has not been acknowledged or addressed. I posed the question because it seemed to me that on certain of the tumorigenic end points, the committee appeared too focused on the first element of the definition (strict statistical treatment of tumor incidence) to the neglect of second element (rate of tumor development). Evidence of enhanced tumor development, including such findings as greater proportions of malignant versus benign tumors, tumor multiplicity, tumor size, decreased tumor latency, etc, may not yield statistical evidence of carcinogenicity, but yet constitute positive evidence of carcinogenicity according to the OSTP definition. If CARC owns this definition, then it should provide more evidence of its utilization in the interpretation of the end points at hand.

11) Incorporation of tumorigenic findings or the absence (or reduced incidences) of the same, at doses considered excessive: Questioned here is the use of tumorigenic findings, or the absence of the same, in a dose group considered excessive by CARC. A prime example is CARC's use of the top two dose groups (6000 ppm and 12000 ppm), considered excessive doses by the committee, for assessing tumorigenicity among male rats, in the combined chronic toxicity/carcinogenicity study in the rat. I contend as improper the discounting of tumorigenic findings of one type at a dose level considered excessive, while utilizing decreased tumorigenic findings of another type in these excessive dose groups to discount positive findings at lower doses considered by the committee to be acceptable. By contrast, I contend that accepting tumorigenic findings at excessive doses is more defensible than accepting as negative a study without findings at excessive doses.

12) Application of general principles of competing toxicity and increased mortality in mitigating expression at excessive doses of a tumorigenic dose-response occurring at acceptable lower doses: In my opinion, having cited authoritative sources, competing toxicity and increased mortality at excessive doses may diminish or even preclude tumorigenic responses identified at lower doses. Furthermore, in consideration of the potential for such compromises of tumor expression to occur at excessive doses, negative or diminished findings at such doses cannot be accepted as negative evidence of carcinogenicity. It is more acceptable, as I understand, to accept positive findings at excessive doses unless (according to EPA's draft Cancer Guidelines) it can be shown such tumorigenic responses resulted from toxicity as opposed to tumorigenicity of the test material. I am not satisfied CARC has made proper use of these concepts, specifically, in discounting certain tumorigenic findings at dose levels considered excessive without demonstrating these arose secondary to toxicity, while on the other hand accepting diminished tumorigenic responses at excessive doses as negative evidence. There have been no statements from CARC clarifying its philosophy.

I must add that in the case of liver tumorigenic responses in female rats in the combined chronic toxicity/carcinogenicity study with malathion, I concur with CARC's interpretation at all doses, including that for the highest dose group, as being consistent with my understand of the principles at issue here, i. e., there is no evidence the tumorigenic response observed at the highest dose, the only dose level considered excessive in females, was due to anything other than the tumorigenicity of the test material.

13) Acceptability of the combined chronic toxicity/carcinogenicity study to evaluate carcinogenic potential in male rats: I have difficulty accepting CARC's decision concerning acceptability of the study as essentially a negative study in male rats, specifically the male F344 rat. Discounting the top two doses as excessive, and accepting the lower dose levels, in my opinion precludes testing at adequately high dose levels. The findings suggest the need for another dose group somewhere between the 500 and 6000 ppm dose groups. It may be the F344 rat is a poor model due to competing toxicity. On the other hand, if CARC accepted the study as demonstrating tumorigenic findings in males at the lower doses, perhaps that would be the end of it. Given the male rat assessment is thus confounded, greater reliance must be placed on findings in females, i.e., as carrying more weight than a single gender finding.

14) Adequacy of Q* method to address risks posed by low dose tumorigenic findings, e.g., liver tumors in the female rat at 100/50 ppm, in the absence of a NOEL: This is a philosophical question raised by me that has not been discussed at any of the CARC meetings as I recall. It is my concern that to the extent low dose tumorigenic findings occur at more elevated incidences than expected based on those incidences at much higher doses (e.g. the female rat liver tumor response), for whatever reason, such as a change of mechanism across the dose range, can the Q* calculation, employing all doses, be expected to address risks posed at the low dose level. I am concerned low dose findings in this assessment, close to those that minimally inhibit cholinesterase are of peculiar concern to the public health, and petition for additional expert comment on the utility of the Q* method to deal with this. This is more a gut feeling than one borne of any particular expertise or evidence I bring to the table. The Q* method has been used by CARC to address public health risks based on the female liver tumorigenic response.

I trust these comments taken in concert with those in the January 27 letter come closer to that which you were seeking. Please be advised I have not seen CARC's final report. I should offer my availability to discuss these topics with any interested individual or group within HED who may be reviewing the subject.

Joyce Shepard, CSWCitizens' Action Committee for ChangeE-Mail: CactionC@jps.netTelephone: 718-279-2069Facsimile: 718-279-3281

Well Lyndon, what can I say, is "our" government really trying to annihilate us with your "registered" POISONS in order to create a "profit"?

(Editor's Note: Okay, at what point do the people start meaning more than profits? Government officials can be sued for malfeasance... is endangering and killing off the population not considered malfeasance?)

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