Conducting evaluations of evidence that are transparent, timely and can lead to health-protective actions.

BACKGROUND: In February 2021, over one hundred scientists and policy experts participated in a web-based Workshop to discuss the ways that divergent evaluations of evidence and scientific uncertainties are used to delay timely protection of human health and the environment from exposures to hazardous agents. The Workshop arose from a previous workshop organized by the European Environment Agency (EEA) in 2008 and which also drew on case studies from the EEA reports on 'Late Lessons from Early Warnings' (2001, 2013). These reports documented dozens of hazardous agents including many chemicals, for which risk reduction measures were delayed for decades after scientists and others had issued early and later warnings about the harm likely to be caused by those agents. RESULTS: Workshop participants used recent case studies including Perfluorooctanoic acid (PFOA), Extremely Low Frequency - Electrical Magnetic Fields (ELF-EMF fields), glyphosate, and Bisphenol A (BPA) to explore myriad reasons for divergent outcomes of evaluations, which has led to delayed and inadequate protection of the public's health. Strategies to overcome these barriers must, therefore, at a minimum include approaches that 1) Make better use of existing data and information, 2) Ensure timeliness, 3) Increase transparency, consistency and minimize bias in evidence evaluations, and 4) Minimize the influence of financial conflicts of interest. CONCLUSION: The recommendations should enhance the production of "actionable evidence," that is, reliable evaluations of the scientific evidence to support timely actions to protect health and environments from exposures to hazardous agents. The recommendations are applicable to policy and regulatory settings at the local, state, federal and international levels.

Lack of data drives uncertainty in PCB health risk assessments.

Health risk assessments generally involve many extrapolations: for example, from animals to humans or from high doses to lower doses. Health risk assessments for PCBs involve all the usual uncertainties, plus additional uncertainties due to the nature of PCBs as a dynamic, complex mixture. Environmental processes alter PCB mixtures after release into the environment, so that people are exposed to mixtures that might not resemble the mixtures where there are toxicity data. This paper discusses the evolution of understanding in assessments of the cancer and noncancer effects of PCBs. It identifies where a lack of data in the past contributed to significant uncertainty and where new data subsequently altered the prevailing understanding of the toxicity of PCB mixtures, either qualitatively or quantitatively. Finally, the paper identifies some uncertainties remaining for current PCB health assessments, particularly those that result from a lack of data on exposure through nursing or on effects from inhalation of PCBs.

Preventable exposures associated with human cancers.

Information on the causes of cancer at specific sites is important to cancer control planners, cancer researchers, cancer patients, and the general public. The International Agency for Research on Cancer (IARC) Monograph series, which has classified human carcinogens for more than 40 years, recently completed a review to provide up-to-date information on the cancer sites associated with more than 100 carcinogenic agents. Based on IARC's review, we listed the cancer sites associated with each agent and then rearranged this information to list the known and suspected causes of cancer at each site. We also summarized the rationale for classifications that were based on mechanistic data. This information, based on the forthcoming IARC Monographs Volume 100, offers insights into the current state-of-the-science of carcinogen identification. Use of mechanistic data to identify carcinogens is increasing, and epidemiological research is identifying additional carcinogens and cancer sites or confirming carcinogenic potential under conditions of lower exposure. Nevertheless, some common human cancers still have few (or no) identified causal agents.

Meeting report: moving upstream-evaluating adverse upstream end points for improved risk assessment and decision-making.

BACKGROUND: Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an "adverse effect" in the context of hazard identification and risk assessment. OBJECTIVES: Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available. DISCUSSION: Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects. CONCLUSIONS: For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population.

Use of mechanistic data in IARC evaluations.

Consideration of mechanistic data has the potential to improve the analysis of both epidemiologic studies and cancer bioassays. IARC has a classification system in which mechanistic data can play a pivotal role. Since 1991, IARC has allowed an agent to be classified as carcinogenic to humans (Group 1) when there is less than sufficient evidence in humans but there is sufficient evidence in experimental animals and "strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity." Mechanistic evidence can also substitute for conventional cancer bioassays when there is less than sufficient evidence in experimental animals, just as mechanistic evidence can substitute for conventional epidemiologic studies when there is less than sufficient evidence in humans. The IARC Monographs have used mechanistic data to raise or lower a classification that would be otherwise based on epidemiologic studies and cancer bioassays only. Recently, the IARC Monographs have evaluated several agents where mechanistic data were pivotal to the overall evaluation: benzo[a]pyrene, carbon black and other poorly soluble particles, ingested nitrates and nitrites, and microcystin-LR. In evaluating mechanistic data, it is important to consider alternative mechanistic hypotheses, because an agent may induce tumors through multiple mechanisms.

Use of carcinogenicity bioassays in the IARC monographs.

Carcinogenicity bioassays generally provide the best means of assessing the potential for a chemical to be a human carcinogenic hazard. The results of carcinogenicity bioassays are usually the key determinants of IARC Monograph evaluations. Along with carcinogenicity bioassays and epidemiological studies, the International Agency for Research on Cancer (IARC) also encourages the consideration of mechanistic data and other relevant data. During 2005 IARC is updating the Preamble to the IARC Monographs, which describes the principles and procedures used in developing the Monographs, including the criteria that guide the evaluations. Proposed revisions to the Preamble make some changes in the criteria for evaluating carcinogenicity in experimental animals to reflect the greater confidence that can be placed in Good Laboratory Practice (GLP) studies. Other changes will give more specific guidance for the evaluation of mechanistic data. Sections on mechanistic data will be given more prominence in future Monographs and will be more closely linked with toxicokinetics. Future Monographs will also include a new section on susceptible individuals, populations, and life stages that will often be based on the understanding of mechanisms. In addition, the draft Preamble discusses IARC's procedures for promoting impartial evaluations by avoiding conflicts of interests and ensuring that working groups are free from interference.

Meeting report: summary of IARC monographs on formaldehyde, 2-butoxyethanol, and 1-tert-butoxy-2-propanol.

An international, interdisciplinary working group of expert scientists met in June 2004 to develop IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans (IARC Monographs) on formaldehyde, 2-butoxyethanol, and 1-tert-butoxy-2-propanol. Each IARC Monograph includes a critical review of the pertinent scientific literature and an evaluation of an agent's potential to cause cancer in humans. After a thorough discussion of the epidemiologic, experimental, and other relevant data, the working group concluded that formaldehyde is carcinogenic to humans, based on sufficient evidence in humans and in experimental animals. In the epidemiologic studies, there was sufficient evidence that formaldehyde causes nasopharyngeal cancer, "strong but not sufficient" evidence of leukemia, and limited evidence of sinonasal cancer. The working group also concluded that 2-butoxyethanol and 1-tert-butoxy-2-propanol are not classifiable as to their carcinogenicity to humans, each having limited evidence in experimental animals and inadequate evidence in humans. These three evaluations and the supporting data will be published as Volume 88 of the IARC Monographs.

Current criteria to establish human carcinogens.

Several national and international health agencies worldwide have established carcinogen identification programs with the aim of identifying the agents and exposures that contribute to the global burden of cancer. These programs have many features in common. IARC's program is described in some detail, with an emphasis on how evaluations can be changed by mechanistic data. Recently, several programs have expanded on the guidance they provide in assessing mechanistic data. The most comprehensive example is EPA's recent draft final Guidelines for Carcinogen Risk Assessment. In all programs, however, the principal role of mechanistic information has been to support the positive results observed in epidemiological studies or to discount the relevance of positive results observed in experimental animal bioassays. An alternative paradigm for carcinogen identification is proposed, one where mechanistic studies have a central role, rather than a supporting one. Under this paradigm, potentially carcinogenic agents would be identified by (1) identifying the key precursor events and processes involved in human cancer and (2) testing to see whether an agent can affect these events and processes. Under this paradigm, which is consistent with a multi-factorial view of carcinogenesis, it might be possible to identify carcinogens through mechanistic understanding alone, without waiting for epidemiological studies or 2-year carcinogenesis bioassays in rats and mice. This paradigm asks the question, "What is a human carcinogen? Is it an agent that we observe to induce tumors, or more generally, an agent with a clear role in tumor development?"

The science and practice of carcinogen identification and evaluation.

Several national and international health agencies have established programs with the aim of identifying agents and exposures that cause cancer in humans. Carcinogen identification is an activity grounded in the scientific evaluation of the results of human epidemiologic studies, long-term bioassays in experimental animals, and other data relevant to an evaluation of carcinogenicity and its mechanisms. In this commentary, after a brief discussion of the science basis common to the evaluation of carcinogens across different programs, we discuss in more detail the principles and procedures currently used by the IARC Monographs program.