July 16, 2001

NTP Office of Liaison and Scientific Review
111 T.W. Alexander Drive
P.O. Box 12233
MD A3-01
Research Triangle Park, NC 27709
liaison@starbase.niehs.nih.gov

Re: Comments on the NTP Endocrine Disruptors Low-Dose Peer Review Final Report

Dear NTP Liaison:

The Alkylphenols & Ethoxylates Research Council (APERC) appreciates the opportunity to submit the following comments on the National Toxicology Program's (NTP) Endocrine Disruptors Low-Dose Peer Review Final Report. APERC members include manufacturers, processors, distributors and users of various alkylphenols, including nonylphenol and octylphenol, two of the specific compounds reviewed as part of the low-dose peer review effort.

APERC fully supported the proposed NTP low-dose peer review. It was our understanding that the primary purpose of the review was to consider the available evidence on the "shape of the dose-response curve for endocrine active substances in the low-dose region." Regrettably, the report that NTP prepared falls far short of this objective. Perhaps more disturbingly, the report fails to live up to the high standards of quality expected from NTP. As discussed in more detail below, APERC believes that an objective review of the available science does not support many of the conclusions and inferences contained in the report.

Much of the difficulty with the report's conclusions are related to the varying definitions of "low-dose" used throughout the report including, at times, the lack of adherence to any specific definition. For example, the Executive Summary states that for this peer review, low-dose effects refer to:

biological changes that occur in the range of human exposures or at doses that are lower than those typically used in the EPA's standard testing paradigm for evaluating reproductive and developmental toxicity. (Page i)

The Executive Summary further notes that the Other Environmental Estrogens and Estradiol Subpanel "developed an operational definition for 'low-dose effects' that was based on the dose-response data for the selected endpoints for each agent under evaluation. Low-dose effects were considered to be occurring when a non-monotonic dose-response resulted in significant effects below the presumed NOEL expected by the traditional testing paradigm." (page iv)

Regrettably, the Subpanel did not adhere to even its own modified definition and essentially considered any difference between treated and control animals occurring at a dose lower than the current NOAEL to be a "low-dose effect." No consideration was given to whether the change was an effect (adverse or not), nor was it considered whether the change represented a non-monotonic dose-response or simply a difference in an unusual endpoint not previously measured. For example, in the case of estradiol, the report suggests that low-dose phenomena occurred based on observations from studies of ovariectomized animals, which found changes in serum prolactin, LH, and FSH levels. However, there is no rationale for associating changes in circulating hormones as an important biological response under such an altered physiological state. Stated differently, the occurrence and significance of changes seen in prolactin, LH, and FSH have not been established in normal animal models. Further, any change in hormone concentration was considered biologically relevant without consideration for consistency with other hormone levels and/or responses or without consideration of whether the change was an increase or decrease.

Specific Comments Regarding Nonylphenol

Executive Summary is Misleading

The Executive Summary clearly states that nonylphenol has "low-dose effects" even though this was not the conclusion presented at the summary of the conference, and this conclusion is not supported by the positions espoused in the body of the report.

In summarizing the overall evaluation with regards to the "low-dose" issue, the Chair of Subpanel 2 indicated that, with regards to nonylphenol, there were "No effects seen." This view was not carried over into the Subpanel's written report, which describes presumed effects at so called low levels. At the same time, the report acknowledges that the significance of these effects are unknown and makes no mention of a non-monotonic dose-response, two criteria specifically stated in the definition of "low-dose effects." The report on page 51 states:

The "low-dose" of nonylphenol is questionable.

Unfortunately, this qualified viewpoint is completely missing from the Executive Summary of the report, which appears to have been written to imply that there are low-dose effects:

Low-dose effects [emphasis added] in F1 rats following dietary exposure to 25 ppm include a decrease in SDN-POA in males, an increase in relative thymus weight, an increase in proliferation of splenic T-lymphocytes stimulated with anti-CD3, and a prolonged estrus in females.

APERC believes that at a minimum, the Executive Summary of the report should have reflected the viewpoints expressed in the body of the report.

The Findings Reported by NTP Do Not Justify a Conclusion of "Low-Dose Effects" For Nonylphenol

The conclusions regarding nonylphenol are stated to be based on observations principally concerning sexually dimorphic nuclei of the preoptic area (SDN-POA) in males, an increase in relative thymus weight, an increase in proliferation of splenic T-lymphocytes stimulated with anti-CD3, and a prolonged estrus in females. For the following reasons, APERC does not believe the reported observations provide sufficient evidence for such a conclusion:

1. The changes reported are not scientifically defensible as adverse effects. The principle measurements reported as "effects," SDN-POA and anti-CD3 effects, are not routinely evaluated in general or reproductive toxicity tests. Therefore, the biological/toxicological significance of these differences between treated and control animals is unknown. In fact, the Subpanel concluded, "As stated above, the SDN-POA changes are difficult to interpret at the moment, as are the anti-CD3 findings." It is also significant that changes in these endpoints resulting from exposure to endocrine active substances, including endogenous hormones, have not been validated as reliable indicators of endocrine activity, nor have these changes been reproduced in the same or other laboratories. The changes mentioned for thymus weight and prolonged estrus were not, to the best of our knowledge, reviewed by the Statistics Subpanel, thus failing to meet an NTP criterion for consideration in the Low-Dose Peer Review. Further, these changes are inconsistent with more robust studies evaluated by the Subpanel and the Statistics Subpanel.

2. There is no evidence of a non-monotonic response. There is no evidence that nonylphenol exhibits a non-monotonic dose-response in any of the studies reviewed for any of the endpoints noted.

3. The purported changes should not be considered to be occurring at "low-doses." Even if, for argument sake, the reported changes were considered to be biologically significant, the fact that they are reported to occur at 25 ppm means they should not be considered "low-dose effects."

4. There is no specificity to the changes stated to be "low-dose effects" for nonylphenol. Based on all of the studies reviewed, there is no specificity to changes in the endpoints. In addition to the stated results for nonylphenol, the changes in SDN-POA and anti-CD3 were observed for several other chemicals at all doses and for several chemicals that have different mechanisms of action. In all cases, there was no clear dose response (monotonic or non-monotonic).

The Additional Recommended Research Will Not Provide Meaningful\Information

The Subpanel concludes with the following recommendation, "More data are needed at the level of ng/kg/day, the human exposure level." Regardless of the significance or relevance of the changes discussed by the Subpanel, there are no data that would suggest such resource-intensive scientific investigations, including the use of experimental animals, are warranted. The lack of evidence for a non-monotonic dose-response for nonylphenol clearly indicates that dosing of nonylphenol in the cited dose range, equivalent to parts per trillion of nonylphenol in animal diets, would not provide meaningful information.

In general, APERC believes that the NTP report would have been significantly more useful and robust if there had been a constant focus on whether available data clearly demonstrated a non-monotonic dose-response in the low-dose region that is common, predictable, and relevant to humans. Instead, the report:

• Did not limit itself to evaluating effects at environmentally relevant exposures but considered effects at any dose, including doses higher than those typically used in standard assays.

• Focused on several observations that may have no relevance to human health, including observations that have no specificity for an endocrine mechanism.

• Drew conclusions from studies that were not designed to assess biological relevance to humans.

• Failed to reach the clear conclusion that nonylphenol does not cause low-dose effects.

In summary, APERC believes that an objective reading of the scientific conclusions for nonylphenol contained in the NTP report does not provide adequate evidence of a "low-dose effect" in accordance with the stated definition, namely, "Low-dose effects were considered to be occurring when a non-monotonic dose-response resulted in significant effects below the presumed NOEL expected by the traditional testing paradigm." Clearly, in the absence of any studies showing any effects in the "low-dose" region, the conclusion of the Subpanel should have been that nonylphenol does not cause low-dose effects.

Please let me know if you have any questions on our comments. Thank you in advance for your consideration.

Sincerely,

Robert J. Fensterheim

 

 

 

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