The Cancer Identification Committee Adopts Guidance Criteria For Identifying Carcinogens

"We now have a set of Guidance Criteria."

With those words, Dr. Tom Mack, Chairman of the Proposition 65 Cancer Identification Committee announced the CIC’s approval of criteria for identifying chemicals for listing as "known to the state to cause cancer." The state’s qualified experts adopted the criteria for identifying carcinogens 14 years after Proposition 65 was passed by voters in November 1986.

Despite having 14 years, the criteria are largely the result of a process with little effective opportunity for public input. Significantly also, the process provided no opportunity for a dialog with the CIC members, the scientists whose interpretations of the criteria will determine to a large extent the implementation of Proposition 65 in the future.

Numerous legal and scientific issues were raised about the criteria during the limited public process. While the CIC made a few significant changes in response to the public comments, many critical issues were summarily ignored with general statements of appreciation and possible modifications in the future.

Issues that the public raised about the criteria for the CIC to consider included concerns that the criteria were inconsistent with the statutory language of Proposition 65, that several parts of the criteria are ambiguous and confusingly written, and that the criteria depart significantly from generally accepted principles as reflected by their inconsistency with criteria of well-recognized scientific bodies. Many of the issues raised and the CIC’s reaction are set out below:

Since the passage of Proposition 65, the state’s qualified experts, initially the Scientific Advisory Panel and later the Developmental and Reproductive Toxicant Identification Committee and the Carcinogen Identification Committee, discussed the need for articulating in writing the criteria for determining whether a chemical is "clearly shown through scientifically valid testing according to generally accepted principles to cause cancer or reproductive toxicity." Criteria for identifying reproductive toxicants were the subject of an SAP meeting in October 1992 and were adopted, after substantial revisions, by the DART Identification Committee in October 1993.

The existence of proposed criteria for identifying carcinogens was first announced on September 3, 1999 in a notice for the CIC’s October 7, 1999 meeting. Discussion and decision by the CIC on criteria was included as a tentative agenda item for that meeting. The public was advised that the criteria could be obtained from a contact person or from the Office of Environmental Health Hazard Assessment’s website. The meeting notice did not contain a process for written comments. Moreover, the short notice time did not allow for a thorough, comprehensive analysis and critique of the proposed criteria.

Most of the public comments submitted prior to the October 7th meeting emphasized the short time to comment and urged OEHHA and the CIC to hold a workshop on the criteria to provide more adequate time to address the many issues raised by the criteria. At the October 7, 1999 meeting, the CIC limited the oral testimony of each commenter to five minutes, postponed the committee discussion and decision until the CIC’s next meeting, and grudgingly provided for a short written comment period.

Numerous comments were submitted by the November 2, 1999 written comment deadline. However, none of them comprehensively reviewed the proposed criteria.

After the November 2, 1999 deadline for written comments, months passed with no word from OEHHA or the CIC concerning the criteria. Significantly, no workshop was held, providing the public with an opportunity for a thorough discussion of the criteria.

On September 22, 2000, OEHHA issued a public notice, announcing that revised criteria were now available, that written comments should be submitted by October 23, 2000, and that the revised criteria would be on the CIC’s November 16, 2000 meeting agenda. The notice also reported that the Chair had requested that written comments be limited to two single-sided pages.

Only two pages were permitted to respond to five pages of criteria that raise innumerable legal and scientific issues. Two pages were barely enough to list the issues raised, least of all to provide a clear explanation of the concerns, to offer alternative language, and to set out a rationale for the proposed alternatives.

A coalition of scientists from multiple, relevant disciplines organized comments that sought to address the more significant issues raised by the proposed criteria. The Scientific Coalition often dealt with the lists of factors contained in the proposed criteria in a general and summary fashion, proposing better-reviewed alternative lists. Even with that approach, the Coalition still needed nine pages for its comments.

Because of the page limitation, the comments, as one might expect, tended to focus on the commenter’s one or two most significant issues. Some commenters appeared to recognize that the CIC was unlikely to make many changes, and they focused on the few changes they thought the CIC might be willing to make.

At the November 16, 2000 meeting, the Chair again limited oral presentations to five minutes each. After the public presentation, the Committee members discussed the criteria and agreed to make selective, substantive changes. They resisted the notion of numerous changes and repeated that the criteria were a work in progress and could be changed further but at a later, indeterminate time.

As noted at the outset, the Chair announced at the end of the criteria discussion that we now have Guidance Criteria. Prior to November 16th, the document was titled "Criteria for Identifying Chemicals for Listing as ‘Known to the State to Cause Cancer’". At the November 16th meeting, Jeff Wilson commented that, "’criteria’ means – is a very absolute method and I think it’s the intent of this Committee to use these as guidelines, not necessarily as, ‘this is the decision tree that we will follow.’" Mr. Wilson suggested the term "Guidance Criteria."

Mr. Wilson’s comment was consistent with Chairman Mack’s announcement at the beginning of the meeting. He said that "…these criteria are basically a set of touchstones for us to use more than anything else…. Their predominant purpose is a sort of tick off list for us to make sure we haven’t forgotten any of the important issues."

Dr. Landolph, a CIC member, expressed satisfaction with the criteria, and said "…it’s good that we re-inform ourselves as to what we should consider. But in the end, we’re going to have to use our scientific judgment…" Later, Dr. Landolph said, "…you know I’m going to do whatever I feel like doing regardless of what the document says."

Other Committee members appeared to de-emphasize the importance of the criteria to their decision making process. They articulated that their role is to exercise scientific judgment. Accordingly, one of the changes that Dr. Mack proposed was to put "…the word ‘Guideline’ in front of ‘Criteria.’"

Obviously, the significance of adding ‘Guidance’ will be revealed in future listing discussions by the CIC. Nevertheless, the signal that the change sends is that the Guidance Criteria are only a checklist, and that the articulation of those factors do not dictate a decision process or outcome.

The proposed criteria raised a number of concerns as to whether the criteria were faithful to the "clearly shown" standard in Proposition 65. The statute provides that the first method for adding a chemical to the Proposition 65 list as a carcinogen is "if in the opinion of the state’s qualified experts it has been clearly shown through scientifically valid testing according to generally accepted principles to cause cancer."

The initially proposed criteria especially waved the "clearly shown" red flag. In paragraph C of the general principles, the original criteria stated that a "weight of evidence" approach shall be used. It then provided that "the body of evidence shall include all indications of carcinogenicity.…" Paragraph D waved the red flag more dramatically by obligating the Committee to list a chemical "…if the weight of evidence indicates that a certain chemical causes cancer…."

The words "indications" and "indicates," were viewed by nearly all of those who submitted comments in 1999 as a serious erosion of the "clearly shown" standard. Addressing that issue was perhaps the most significant change made in the revised criteria released on September 22, 2000. Paragraph C of the general principles was changed to say "…the body of evidence shall include all evidence bearing on the issue of carcinogenicity…." Paragraph D of the general principles was changed to say that the Committee is obligated to list a chemical "…if the weight of scientific evidence clearly shows that a certain chemical causes cancer…."

Also, OEHHA’s chief counsel, Colleen Heck, made clear at the November 16, 2000 meeting that the criteria are secondary to the statutory standard and cannot be implemented inconsistently with the statute. She stated, "…in the end, as in the beginning, the basis of any listing decision will be whether or not a chemical meets the criterion in the statute. That is, whether or not it’s been clearly shown through scientifically valid testing and according to general principles to cause cancer. The Guidelines, the Criteria, really help inform your discussion and your decision making as to that standard. It does not create a new standard."

Perhaps Ms. Heck’s comment can be construed as addressing other concerns raised that certain language in the proposed criteria were ambiguous, creating the potential for inconsistencies with the clearly shown standard. For example, paragraph B of the General Principles contains the statement that "[t]hese criteria are intended to give the CIC maximal flexibility in evaluating all pertinent scientific information in determining whether a chemical is known to the State to cause cancer.

John Hunter, testifying at the November 16th meeting, pointed out that the phrase, "maximal flexibility," is ambiguous and that the statute limits the CIC to a standard of "clearly shown through scientifically valid testing." As Mr. Hunter stated, the statute does not give the CIC "maximal flexibility."

Also, the Scientific Coalition, in its written comments, emphasized that the statute imposes a standard that is more rigorous than that used by other cancer-identifying bodies. In addition, the criteria should direct and focus the CIC members and provide the regulated community with a sense of how the CIC will identify carcinogens. Maximally flexible criteria serve no purpose.

A related issue, also raised by Mr. Hunter, was a phrase contained in paragraph D of the General Principles. The first sentence appears to quote the clearly shown standard contained in Proposition 65 until it adds at the end, "without further restriction." The last phrase added ambiguity to the well-recognized statutory standard. What was its purpose? What does it mean?

The CIC did not address either issue during the Committee discussion on November 16th. Hence, no clarity was provided as to the meaning. The significance of the "maximal flexibility" phrase may be no more than that the DART Identification Committee’s criteria contains the same phrase, and the CIC is not about to confer less discretion on itself than the DART Identification Committee has.

Was Ms. Heck signaling that these phrases are meaningless because as the Scientific Coalition said in its comments, "[t]he statutory standard is the statutory standard"? These criteria do not change the clearly shown standard.

Ambiguous provisions in the proposed criteria were not limited to the legal standards. They abounded in criteria relating to scientific concepts. At times, the criteria introduced one subject and the following list of factors related to another subject. Some of the list of factors were so nebulous that questions were raised whether the drafters intended to establish criteria substantively different than those used by other bodies that identify and characterize carcinogens. Or are the drafters paraphrasing criteria used by other scientific bodies, but doing so in a very imprecise manner.

Commenters approached these ambiguities differently. Some raised questions about the meaning of a few phrases not typically used in toxicological circles. Others criticized the entire list of factors. For example, the Scientific Coalition recommended that the nebulous list of factors be replaced with the relevant list of factors contained in the United States Environmental Protection Agency’s 1999 Guidelines for Carcinogen Risk Assessment.

Paragraph E of the General Principles provides a prime example of a misconnect between the introduction and the following list of factors. The first sentence of paragraph E states "the application of causation criteria requires scientific judgments which can only be based on experience, not only with the interpretation of epidemiological studies or animal carcinogenicity experiments in general, but with the circumstances of exposure, the physical and demographic setting, the nature of classification, including pertinent clinical and histologic schemata and the qualifications of the investigator."

While the sentence begins referencing causation criteria, it then contains a list of factors that appear to be related to the validity or quality evaluation of studies. Dr. James Coughlin, testifying at the November 16th meeting, urged the CIC to use the well-accepted Bradford-Hill criteria as the CIC’s causation criteria. He suggested re-writing the sentence as follows, "The application of causation criteria requires scientific judgment that evaluates a temporal relationship, consistency, magnitude of the association, biological gradient, specificity of the association, biological plausibility, and coherence." Dr. Coughlin pointed out that the US EPA had incorporated the Bradford-Hill criteria into its 1999 Guidelines.

Continuing with his testimony, Dr. Coughlin criticized the list of factors relating to the validity of epidemiological studies as being an incomplete and ambiguous articulation of the parameters necessary for assessing the adequacy of epidemiological studies. Dr. Coughlin emphasized the work that had gone into US EPA’s development of its list of well-recognized parameters for determining the validity of epidemiological studies. Accordingly, he recommended that the CIC replace its incomplete and ambiguous list with the well-developed, comprehensive EPA list of factors.

Dr. Coughlin also recommended that the factors included in the proposed guidelines for determining the causal relationship between exposure and cancer in epidemiological studies be replaced. In Dr. Coughlin’s presentation, he pointed out that EPA’s draft Guidelines contain a well-reasoned statement of principle and then a list of factors that increase the weight of evidence and a list of factors that decrease the weight of evidence in determining causation.

The ambiguities in the scientific principles that are articulated in the proposed criteria exist in the factors relating to animal studies just as they do in the factors relating to epidemiological studies. The same misconnect between the headings and the list of factors is present in the animal study section of the criteria as well. More important, of course, is the ambiguity of the factors relating to the valid animal studies and the factors relating to weight of evidence to determine causation.

Dr. George Cruzan, testified at the November 16th meeting, referred to both the validity and weight of evidence factors as extremely nebulous. Testifying as a Board-certified toxicologist, he spent much of his five minutes detailing the ambiguous provisions. Once again, he urged the CIC to replace their validity and weight of evidence criteria with the validity and weight of evidence criteria developed and contained in the US EPA 1999 draft Guidelines. Dr. Cruzan emphasized that the extent to which the CIC uses criteria that are articulated similarly to those used by other scientific bodies is the extent to which the CIC facilitates common understanding and greater consistency in the resulting decisions.

The proposed criteria introduced the set of factors pertaining to the validity of epidemiological studies and animal studies by saying "interpretation of the evidence is greatly facilitated by the availability…" of the listed factors. Both Dr. Cruzan and Dr. Coughlin questioned the appropriateness of the term "facilitated." Dr. Cruzan, in particular, argued that the list of validity factors are essential to a study, that if these factors are not present, the study does not meet the bare minimum for validity and, therefore, should not be included in the weight of evidence.

During the Committee discussion, Dr. Landolph stated that he agreed with Dr. Cruzan’s comments and that the criteria should be strengthened. He suggested saying that "…the specific details are crucial to the interpretation of the animal studies…." Dr. Mack responded saying, "You think that ‘facilitated’ is not strong enough?" Dr. Landolph confirmed that he agreed with Dr. Cruzan in that the criteria should say that the "specific details are crucial or important to the interpretation of the animal studies."

Dr. Landolph’s suggestion, however, died on the altar of flexibility. Dr. Mack stated, "I actually prefer ‘facilitated.’ And the reason I do is it provides us with a little more flexibility." He added, "Rather than locking us into a list, ‘facilitated’ allows us to weigh each of these lines and I think that’s a better way to go."

Despite a fairly critical review of the manner in which the critical scientific criteria were articulated and despite the appeal from Dr. Coughlin and Dr. Cruzan and the Scientific Coalition, the CIC made no move toward conforming its criteria with that of US EPA or any other authoritative body. It’s not that the Committee was unsympathetic to the written and oral comments. Rather, it seemed to recognize no need to make any changes.

At the beginning of the Committee’s discussion of the criteria following the public comment period, Dr. Mack said that "…most of the requests that people are making are in the guise of a different way to skin a cat." Later, he repeated that phrase, saying "Again, I would say that there are many ways to skin a cat and most of things that have been proposed, I’d find reasonable also. But I think we’ve taken care of it in other ways in the document as it stands. And I think actually when I was constructing this, I looked at the EPA draft that I had available to me and chose not to use some of the specific things that you suggested for specific reasons, not to say that they’re not good. It’s just a matter of how one lays it out."

Dr. Froines said, "So I have a criteria for the Criteria, in essence. And my criteria is that we should not establish any criteria that is in conflict with the criteria that is used within the context of authoritative bodies." In response, Dr. Mack said, "I tried very very hard not to make anything in conflict and I don’t think there is. If you find something, I’d be willing to consider changes. But I think it’s completely consistent. On the other hand, we have a different mandate than IARC does, so we have to pay attention to the wording of the initiative. And I think it’s also consistent with that."

At that point in the discussion, it appeared that the CIC members favored consistency with other scientific bodies that identify carcinogens and that if any difference existed, it was to ensure that the criteria are consistent with the Proposition 65 statutory standard. That impression, however, was short-lived. Within a few minutes, Dr. Mack, referring to the IARC criteria, concluded that Proposition 65 gave the CIC "…a little bit more general mandate…. And by that token, this [criteria] is a little bit more general. It’s a little bit more permissive, if you want to think of it that way." Froines responded positively saying, "Well, I think that’s a good idea because it gives us more flexibility." Dr. Mack agreeing, said, "More flexibility, exactly."

The most logical interpretation to give to the discussion by the CIC members is that they value consistency with the criteria followed by other scientific bodies but appreciate that Proposition 65 sets a different standard, and that their flexibility in assessing scientific evidence is to be constrained only by the statutory standard and not by any set of criteria or guidelines.

Prior to the November 16th meeting, certain commenters had raised other specific ambiguities in the criteria in their written submissions. For example, the phrases "dosage of exposure," "the degree of malignancy or malignant potential," and "especially low dosage" were specifically identified as phrases unknown in the toxicological world. The commenters asked for clarification or revisions that would be consistent with toxicological usage. No Committee member acknowledged these comments or the ambiguous phrases. Accordingly, the Committee had no discussions with respect to these phrases and offered no clarity about their meaning or how they are to be interpreted or applied in the future.

The CIC did consider two other issues raised by commenters as ambiguous phrases. The proposed criteria, after first referring to the "weight of evidence," began to use the phrase "weight of accumulated evidence." The Scientific Coalition raised in its written comments the question about the significance of the phrase "accumulated evidence." Was the CIC intending to mean something different than the weight of evidence which has a well-understood meaning? During the hearing, John Hunter, Dr. George Cruzan, and Dr. James Coughlin all asked the CIC what, if anything, was intended by the phrase. They also recommended that the word "accumulated" should be removed so as to make clear that the CIC has the same meaning for the phrase weight of evidence as other scientific bodies. The CIC, following Dr. Mack’s recommendation, agreed to make that change.

The Guidance Criteria that the CIC adopted contains most of the ambiguities identified by Dr. Cruzan and Dr. Coughlin at the hearing and by the Scientific Coalition and other commenters who submitted written comments. It appears that some of the ambiguity is intentional, designed to provide the CIC with "maximal flexibility." The incomplete list and imprecise paraphrases provide both an opportunity and a necessity for the interested public to offer better-defined interpretations. These proposed interpretations may be supported by reference to criteria used by other scientific bodies. Certainly, the CIC’s commitment to maximal flexibility means that it must be open to consider other criteria as it seeks to follow its Proposition 65 mandate.

While significant emphasis had been given to the Proposition 65 standard of clearly shown, the balance of the standard is clearly shown "through scientifically valid testing according to generally accepted principles." The proposed criteria contained statements and factors that are inconsistent with the "generally accepted principles" standard.

John Hunter raised the issue of negative studies in referring to the general principles where the criteria seemed to disfavor the use of negative studies. The Scientific Coalition also raised it specifically with respect to paragraph F of the General Principles. There, the revised proposed criteria stated, "Negative tests can rarely offer strong evidence against carcinogenicity."

The Scientific Coalition pointed out in its written comments that negative studies can raise questions about the replicability of the initial study. Even EPA says that "findings of a large excess risk in a single study must be balanced against the lack of consistency as reflected by null results from other equally well-designed and well-conducted studies." Negative studies may highlight study design problems in the first study or it may highlight confounding factors. A well-conducted negative study can be strong evidence particularly against a poorly-conducted positive study. Further, multiple negative studies add significant weight against carcinogenicity.

During the Committee’s discussion on the criteria, Dr. Felton raised the comments about negative data and said he thought the CIC should "…emphasize that good negative studies are really important." Substantial discussion was had by the Committee in how to revise the criteria to give the appropriate emphasis to negative studies. Dr. Felton worked diligently during the Committee’s discussion to draft language.

The pundit who described the specter of language drafted by a committee would have felt vindicated by the Committee’s effort to revise the criteria relating to negative studies. The members, finally recognizing the futility of drafting by committee, authorized the Chair, Dr. Thomas Mack, to write the final language. The extent to which negative studies will play a role in the CIC’s deliberations will not become known until the final revised Guidance Criteria are released sometime in early 2001.

The Criteria’s proposed limitation on the use of mechanistic data raised another serious issue of consistency with the generally accepted principles standard. The criteria of concern is found in paragraph D of the General Principles and is as follows, "Thus if the weight of scientific evidence clearly shows that a certain chemical causes invasive cancer in humans, or that it causes invasive cancer in animals (unless the mechanism of action has been shown not to be relevant to humans), the Committee is required to identify that chemical for listing." The CIC appears to be saying that it would consider only mechanistic data sufficient to show that the animal data is not relevant to humans.

The Scientific Coalition pointed out in its written comments that "the sentence relating to mechanism of action is inconsistent with Proposition 65 and inconsistent with the criteria used by reputable scientific bodies identifying carcinogens. It suggested, as did other commenters submitting written statements, the following revised language, "Thus, if the weight of scientific evidence clearly shows that a certain chemical causes invasive cancer in humans -- or in the absence of human data – that it causes invasive cancer in animals, through a mechanism appropriate for extrapolation to humans, the Committee will normally identify that chemical for listing."

Dr. Jay Murray raised the mechanistic data issue at the November 16th meeting. Following the lead of the CIC members who emphasized their desire for having maximal flexibility, Dr. Murray urged the Committee to revise the criteria relating to mechanism of action. He pointed out that it is unlikely that the Committee intended to restrict the mechanistic data that it could consider. However, the effect of the proposed criteria is to limit the mechanistic data that the Committee can consider. He pointed out that some mechanistic data do not show that animal results are not relevant to humans, but instead suggest a probability that the animal data are not relevant. He emphasized that the criteria should permit the Committee "to evaluate all mechanistic data, not just data that shows certain animal results are not relevant to humans."

Dr. Murray pointed out that the Presidential/Congressional Commission on Risk Assessment and Risk Management identified a number of rodent tumor mechanisms that may not be relevant to human cancer risk. The examples identified by the Commission include a-2m globulin-induced male rat kidney induced tumors, a local hyperplasia for stomach tumors, reactive hyperplasia from cytotoxic precipitated chemicals causing male rat bladder tumors, overwhelming the current mechanism causing rat lung tumors, and sustained excessive hormonal stimulation causing thyroid tumors.

Dr. Murray pointed out that the CIC in reviewing a chemical at an earlier meeting assigned weight to mechanistic data that probably rendered extrapolation to humans inappropriate, but did not show that the animal data was irrelevant. He also pointed out that "examining all relevant mechanistic data is a generally accepted principle of cancer hazard identification. Limiting mechanistic data to only what demonstrates irrelevance to humans, is not."

Finally, Dr. Murray recommended that the CIC revise the language and offered two alternatives. He stated that he preferred the suggestion that he had made a year ago, which was to modify that sentence similarly to that recommended by the Scientific Coalition and set out above. His second alternative was to modify the phrase relating to mechanism of action to say "unless mechanism of action is probably not relevant to humans."

While flexibility appeared to be the greatest value in justifying the way in which many of the criteria were articulated, the Committee members failed to respond to Dr. Murray’s appeal that they protect their flexibility. Similarly, the appeal that a less restrictive limitation on mechanistic data is required by the "generally recognized principles" standard had no impact on the Committee members. Not one Committee member said one thing about this criteria.

The proposed criteria contained a potentially dramatic departure from generally accepted principles in paragraph F. The criteria raising the issue is articulated as follows: "Whether evaluating the evidence for carcinogenicity in animals or humans, C.I.C. members may make judgements utilizing other, more indirect, scientifically valid observations obtained using generally accepted methods and principles. Such information may derive from studies of genetic toxicology or DNA repair using in vitro methods, cultured mammalian cells, or living prokaryotes, lower eukaryotes, plants, or insects, although changes induced in whole mammals must be considered more pertinent."

The Scientific Coalition was concerned that the criteria proposed to use "indirect" observations to lower the standard for listing chemicals as carcinogens. It pointed out that such a use would be inconsistent with Proposition 65 and sound scientific principles. It argued that the only data that can be used to list a chemical is that derived from well-conducted human or animal studies. It pointed out that previous iterations of the state’s qualified experts did not use indirect studies either to list or to support the listing of chemicals.

Dr. Mack responded to those concerns during the Committee’s discussion on the criteria. He said that he wanted to address the "concern about our making a judgment on the basis of information which doesn’t come from either animal or human studies. I just don’t think that’s a realistic concern. I think the way we worded that phrase was, ‘…whether evaluating the evidence for carcinogenicity in animals or in humans’…. No, I don’t think that’s a concern. I mean, obviously we considered it… but I don’t think we’re ever going to be in a situation where we’re basing a listing solely on [that] data." After Dr. Mack made his clear statement that indirect data would not be the basis of listing, he then added some degree of uncertainty by saying, "I’m not making policy when I’m saying this, I’m making a reasonable guess."

The issue of how indirect data is to be used, like other provisions in the criteria, will become known only during the CIC’s future interpretations. The future with respect to this issue of indirect data was relatively immediate.

Later, during the morning of November 16th, the Committee considered whether to add 4-methylquinoline to the Proposition 65 list as a carcinogen. The vote was 5 to 1 not to list.

The one vote was cast by Dr. Froines who did so on the basis that the chemical structure of 4-methylquinone was similar to a known carcinogen. After the vote was taken, Dr. Froines then said, "I think that if we’re going to say in our criteria that we’re going to use structure activity, we’re going to use mechanism, we’re going to use genotoxicity, we’re going to use blah blah blah, we’re going to be flexible and we’re going to use all the science, then we should use all the science and we shouldn’t only use the animal and the human because – or else we should say that’s what we’re going to do."

Dr. Mack responded, "But saying we’re going to use doesn’t mean we’re going to exclusively use it. In other words, I think there’s no question that it will and has pushed us over the line when there are ambiguous animal studies. But we haven’t, I don’t think, so far ever used it alone and I’m generally against using it alone." Dr. Froines then emphasized that, "My vote was on the issue of the structural similarity in quinoline and I think that that is a very close call in itself as well." Dr. Mack then noted that the issue was one of weighing the indirect evidence, not a question of whether it was to be considered.

The issue of indirect evidence was raised and debated within an hour after Dr. Mack announced that we now have a set of Guidance Criteria. We can undoubtedly expect to see this issue revisited. As Dr. Froines noted in the October 1999 CIC meeting, all of the low-lying fruit has been picked. The chemicals yet to be considered are those for which very limited animal and human data is available. The pressure to use indirect data such as structure, metabolites, and genotoxicity data and mechanism of action may very well intensify.

Written comments submitted to the CIC last year as well as this year raised other examples of provisions in the Criteria that are inconsistent with the "generally accepted principles" standard. This is particularly true with respect to the causation criteria relating to animal studies.

Under the heading of causation being enhanced, reference is made to tumors found to occur in significant excess in two distinct species, in two genders of a species, or two different experiments carried out in two different laboratories under different protocols. The point was made that considering tumors in the two genders of the same species to enhance plausibility of causation is not generally accepted as a sound scientific principle.

In addition, the proposed Criteria provide that a single study in one species might be considered to provide sufficient evidence of carcinogenicity if the tumors occur to an unusual degree. Again, written comments were submitted pointing out that other scientific bodies do not consider a single study in one species to ever be sufficient evidence of carcinogenicity.

Other bodies also have made it clear that if the background rate is high or that the species or strain is known to have an unusually high susceptibility to tumors, that these circumstances would never give rise to a finding that the tumors occurred to an unusual degree. The commenter noted, for example, that the induction of hepatocellular tumors in B6C3F1 mice should not be considered to an unusual degree regardless of the frequency because of the unusually high susceptibility of that strain to chemical-induced tumors.

Once again, no CIC member acknowledged the issues raised in these written comments. Accordingly, no discussion ensued and no greater understanding exists with respect to how the CIC will evaluate data relating to both genders of a single species or what it will consider to be "to an unusual degree when the data is limited to a single study in a single species.

Dr. Mack was right. We now have a set of Guidance Criteria. An unfortunate reality, is that the Guidance Criteria were not sharpened by a rigorous public discussion. Many, although not all, concerns with the Guidance Criteria result from imprecise paraphrasing of criteria articulated by other scientific bodies.

The realities that remain unchanged are that while the Guidance Criteria appear to be interpretations of the statutory standards contained in Proposition 65, the truth of the matter is that the Guidance Criteria will be interpreted and reinterpreted on the basis of the statutory standards. The standard that a chemical is to be listed only if it is clearly shown through scientifically valid testing according to generally accepted principles remains the one immutable criterion., Dr. Mack did state on November 16th with respect to the clearly shown standard, "We can lament it, but that’s all." Nevertheless, he followed its dictate in voting not to list two of the chemicals that the CIC considered later that same morning.

The Guidance Criteria may complicate the public’s task in preparing written materials and oral testimony for the CIC when it considers listing chemicals. It may make it more complex because these Guidance Criteria have to be addressed; they have to be interpreted and like any statement of law, the first few "cases" may very well determine the interpretation given them. However, comment and testimony concerning the actions of other scientific bodies and what are generally accepted principles may become even more important in the future because of the need to assure that these Guidance Criteria do not lead the CIC away from the statutory standards.

The effect and value, if any, of the Guidance Criteria will be revealed only through their future use by the CIC as it makes listing decisions. The Guidance Criteria may become landmarks that guide both the CIC and the regulated community. On the other hand, the concept of maximal flexibility may mean that the Guidance Criteria result in no predictability of how the CIC will assess scientific data.

Also, the CIC has committed that the Guidance Criteria is a living document. It has agreed to consider requested modifications at any time. Obviously, a wholesale repetition of comments just made would not be well-received by the Chair or other members of the CIC. However, a focus on incremental modification, addressing first either the criteria that are the most inconsistent with generally accepted principles or the most ambiguous would be difficult for the CIC to ignore.

The CIC has made a commitment to being open to changes. The ball is now in the public’s court both as to the time and issue to raise with the CIC. Certainly, the work that has been done to date provides numerous opportunities for continuing to work with the CIC on its Guidance Criteria.