Scientific peer review to inform regulatory decision making: leadership responsibilities and cautions.

The article offers insights on the peer-review process as it relates to scientific and technical reports used to inform regulatory decisions. Used effectively, peer review is a powerful tool for advising organizational leaders whether the scientific foundations of their decisions can be expected to withstand scrutiny as rule-making products move through interagency reviews, public comment and stakeholder processes, congressional oversight, and judicial review. The emphasis is "heads up" rather than "how to." That is, without delving into myriad technical and administrative details, the discussion highlights nine fundamental "leadership responsibilities" that determine the nature and course of peer review.

Overview: Using mode of action and life stage information to evaluate the human relevance of animal toxicity data.

A complete mode of action human relevance analysis--as distinct from mode of action (MOA) analysis alone--depends on robust information on the animal MOA, as well as systematic comparison of the animal data with corresponding information from humans. In November 2003, the International Life Sciences Institute's Risk Science Institute (ILSI RSI) published a 2-year study using animal and human MOA information to generate a four-part Human Relevance Framework (HRF) for systematic and transparent analysis of MOA data and information. Based mainly on non-DNA-reactive carcinogens, the HRF features a "concordance" analysis of MOA information from both animal and human sources, with a focus on determining the appropriate role for each MOA data set in human risk assessment. With MOA information increasingly available for risk assessment purposes, this article illustrates the further applicability of the HRF for reproductive, developmental, neurologic, and renal endpoints, as well as cancer. Based on qualitative and quantitative MOA considerations, the MOA/human relevance analysis also contributes to identifying data needs and issues essential for the dose-response and exposure assessment steps in the overall risk assessment.

The human relevance of information on carcinogenic modes of action: overview.

Risk assessment policies and practice place increasing reliance on mode of action (MOA) data to inform conclusions about the human relevance of animal tumors. In June 2001, the Risk Science Institute of the International Life Sciences Institute formed a workgroup to study this issue. The workgroup divided into two subgroups, one developing and testing a "framework" for MOA relevance analysis and the other conducting an in-depth analysis of peroxisome proliferation-activated receptor (PPAR)alpha activation as the MOA for some animal carcinogens. This special issue of Critical Reviews in Toxicology presents the scientific reports emerging from this activity. These reports serve several purposes. For risk assessors in and out of government, they offer a new human relevance framework (HRF) that complements and extends existing guidance from other organizations. Regarding the specific MOA for peroxisome proliferating chemicals, these reports offer a state-of-the-science review of this important MOA and its role in tumorigenesis in three different tissues (liver, testis, and pancreas). The case studies in these reports present models for using MOA information to evaluate the hazard potential for humans. The cases also illustrate the substantial impact of a complete human relevance analysis, as distinct from an animal MOA analysis alone, on the nature and scope of risk assessment.

A framework for human relevance analysis of information on carcinogenic modes of action.

The human relevance framework (HRF) outlines a four-part process, beginning with data on the mode of action (MOA) in laboratory animals, for evaluating the human relevance of animal tumors. Drawing on U.S. EPA and IPCS proposals for animal MOA analysis, the HRF expands those analyses to include a systematic evaluation of comparability, or lack of comparability, between the postulated animal MOA and related information from human data sources. The HRF evolved through a series of case studies representing several different MOAs. HRF analyses produced divergent outcomes, some leading to complete risk assessment and others discontinuing the process, according to the data available from animal and human sources. Two case examples call for complete risk assessments. One is the default: When data are insufficient to confidently postulate a MOA for test animals, the animal tumor data are presumed to be relevant for risk assessment and a complete risk assessment is necessary. The other is the product of a data-based finding that the animal MOA is relevant to humans. For the specific MOA and endpoint combinations studied for this article, full risk assessments are necessary for potentially relevant MOAs involving cytotoxicity and cell proliferation in animals and humans (Case Study 6, chloroform) and formation of urinary-tract calculi (Case Study 7, melamine). In other circumstances, when data-based findings for the chemical and endpoint combination studied indicate that the tumor-related animal MOA is unlikely to have a human counterpart, there is little reason to continue the risk assessment for that combination. Similarly, when qualitative considerations identify MOAs specific to the test species or quantitative considerations indicate that the animal MOA is unlikely to occur in humans, such hazard findings are generally conclusive and further risk assessment is not necessary for the endpoint-MOA combination under study. Case examples include a tumor-related protein specific to test animals (Case Study 3, d-limonene), the tumor consequences of hormone suppression typical of laboratory animals but not humans (Case Study 4, atrazine), and chemical-related enhanced hormone clearance rates in animals relative to humans (Case Study 5, phenobarbital). The human relevance analysis is highly specific for the chemical-MOA-tissue-endpoint combination under analysis in any particular case: different tissues, different endpoints, or alternative MOAs for a given chemical may result in different human relevance findings. By providing a systematic approach to using MOA data, the HRF offers a new tool for the scientific community's overall effort to enhance the predictive power, reliability and transparency of cancer risk assessment.