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The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.

A key element of risk assessment is accounting for the full range of variability in response to environmental exposures. Default dose-response methods typically assume a 10-fold difference in response to chemical exposures between average (healthy) and susceptible humans, despite evidence of wider variability. Experts and authoritative bodies support using advanced techniques to better account for human variability due to factors such as in utero or early life exposure and exposure to multiple environmental, social, and economic stressors.This review describes: 1) sources of human variability and susceptibility in dose-response assessment, 2) existing US frameworks for addressing response variability in risk assessment; 3) key scientific inadequacies necessitating updated methods; 4) improved approaches and opportunities for better use of science; and 5) specific and quantitative recommendations to address evidence and policy needs.Current default adjustment factors do not sufficiently capture human variability in dose-response and thus are inadequate to protect the entire population. Susceptible groups are not appropriately protected under current regulatory guidelines. Emerging tools and data sources that better account for human variability and susceptibility include probabilistic methods, genetically diverse in vivo and in vitro models, and the use of human data to capture underlying risk and/or assess combined effects from chemical and non-chemical stressors.We recommend using updated methods and data to improve consideration of human variability and susceptibility in risk assessment, including the use of increased default human variability factors and separate adjustment factors for capturing age/life stage of development and exposure to multiple chemical and non-chemical stressors. Updated methods would result in greater transparency and protection for susceptible groups, including children, infants, people who are pregnant or nursing, people with disabilities, and those burdened by additional environmental exposures and/or social factors such as poverty and racism.

Much progress has happened in understanding developmental vulnerability to preventable environmental hazards. Along with the improved insight, the perspective has widened, and developmental toxicity now involves latent effects that can result in delayed adverse effects in adults or at old age and additional effects that can be transgenerationally transferred to future generations. Although epidemiology and toxicology to an increasing degree are exploring the adverse effects from developmental exposures in human beings, the improved documentation has resulted in little progress in protection, and few environmental chemicals are currently regulated to protect against developmental toxicity, whether it be neurotoxicity, endocrine disruption or other adverse outcome. The desire to obtain a high degree of certainty and verification of the evidence used for decision-making must be weighed against the costs and necessary duration of research, as well as the long-term costs to human health because of delayed protection of vulnerable early-life stages of human development and, possibly, future generations. Although two-generation toxicology tests may be useful for initial test purposes, other rapidly emerging tools need to be seriously considered from computational chemistry and metabolomics to CLARITY-BPA-type designs, big data and population record linkage approaches that will allow efficient generation of new insight; epigenetic mechanisms may necessitate a set of additional regulatory tests to reveal such effects. As reflected by the Prenatal Programming and Toxicity (PPTOX) VI conference, the current scientific understanding and the timescales involved require an intensified approach to protect against preventable adverse health effects that can harm the next generation and generations to come. While further research is needed, the main emphasis should be on research translation and timely public health intervention to avoid serious, irreversible and perhaps transgenerational harm.

Toxic substances have been of public concern at least since Rachel Carson's The Silent Spring. Yet in many ways we are far short of coping adequately with the problems posed by these invisible, silent, harmful intruders: we are forced to address them “through a glass darkly.” The research described in this paper, reflecting broadly humanistic themes, represents more than a decade's work directed at some of the philosophic, scientific, regulatory and legal problems encountered in trying to assess and ultimately control toxicants in our lives.The vanishingly small size of toxicants makes them difficult to address. They are difficult to detect, identify, and understand whether they pose problems for humans. Each new substance often poses a different detective problem. In turn these difficulties are exacerbated by traditional scientific burdens of proof and legal contexts in which the problems must be considered. However, the legal regulation of toxic substances by the tort (or personal injury) or regulatory law can be addressed by sensitively designing scientific and legal burdens of proof for the legal and public health problem in question. In sections (V) and (VI) of this paper, I describe some approaches to ameliorating some of the proof and institutional design problems that currently preclude more expeditious prevention of public health problems from toxic substances. Some of this research has been incorporated into California legal procedures and aspects of it have been argued for in legal journals.Beyond the specifics of the particular research, this long-term project also manifests some features typical of humanistic research. It addresses aspects of a problem to which C. P. Snow called attention in "Two Cultures and the Scientific Revolution" (1959). He was concerned that the loss of "even the pretense of a common [intellectual scientific and humanistic] culture" was serious for our "creative, intellectual and . . .our normal life" and "dangerous in the most practical terms." Inter alia, we would not be confronting major social problems with the best knowledge we had for solving them. Thirty years later intellectual fields in contemporary universities, especially scientific and humanistic fields, may be even more isolated than when he wrote. The described research had to bring disparate fields together to address problems posed by toxicants.This research had to be both empirically and institutionally rich, informed by the fields of toxicology and epidemiology as well as the law in order to contribute to the subject and to provide appropriate background for it. Detailed scientific and institutional research helps to reveal hidden philosophic issues and to suggest solutions to some of the problems.In order to address problems with multidisciplinary or interdisciplinary features, we also need to re-organize how we think, change our "organization of knowledge.” Broadly speaking, there are at least two different approaches. One is to work with teams of people to address a problem, bringing toxicologists, epidemiologists, biologists, policy experts and philosophers together to ensure that there is appropriate expertise to speak to different technical issues in law and science, and to provide a sound basis for philosophizing, which I did for some of the research papers. The other integrates the relevant knowledge in individuals to speak to the issues. Both enrich intellectual resources: the first to some extent broadens the culture and expertise of all who participate in the project; the second broadens the intellectual resources of the individuals who integrate the knowledge.Finally, the research is quintessentially philosophic and humanistic. Finding defensible approaches for utilizing science in the regulatory and tort law to protect humans from toxicants are meta-scientific and meta-legal issues about the desirability and defensibility of different relationships between science and the law. They also involve both microscopic and macroscopic philosophic accounts and interpretations of law and science. At the macro-level the main aim has been to provide appropriate understanding for utilizing scientific evidence in environmental health and in toxic tort law. At a more micro-level the research focused on how we interpret scientific evidence about particular suspected toxicants when it was fraught with considerable uncertainty and laden with normative considerations. How should we regulate toxic substances “through a glass darkly?”

The idea of a precautionary principle (or precautionary principles) is beginning to come to the wider attention of the environmental community, governmental agencies, regulatory agencies. and the regulated community. Different precautionary principles have not been specified in detail, and, of course, this is difficult to do. Yet some specification must be done in order to understand it better and, if it is to be used for specific action-guidance, to implement it. Moreover, it is Important to understand more about the principle, its background assumptions and its comparison with other principles to which we might subscribe. This paper explores aspects of the PP and its background assumptions and presuppositions, comparing them with those for risk assessment and other statements of the PP. It also briefly indicates how it resembles legal principles in addressing problems of uncertainty. Finally, it recapitulates two possible versions of the PP and suggests an application of it for an emerging threat to the environment and public health. This review suggests the PP has plausible applications and is not the radical principle some have suggested. Keywords: precautionary principle, presuppositions, risk assessment, uncertainties