In Pursuit of Safety 100 Years of Toxicological Risk Assessment

Transcription

1 Silent Spring: Elixirs of Death In Pursuit of Safety 100 Years of Toxicological Risk Assessment Prepared in Commemoration of the 50th Anniversary of the Publication of Rachel Carson s Silent Spring PRESENTED TO: The Royal Society of Chemistry Burlington House, Piccadilly, London PRESENTED BY: Joseph V. Rodricks, PhD, DABT ENVIRON, Arlington, Virginia, USA 02 October For the first time in the history of the world, every human being is now subjected to contact with dangerous chemicals from the moment of conception to death. (Chapter 3) 2 Silent Spring: One in Every Four A 100-Year Struggle The most determined effort should be made to eliminate those carcinogens that now contaminate our food, our water supplies, and our atmosphere, because these provide the most dangerous type of contact minute exposures, repeated over and over throughout the years. (Chapter 14) The following questions about chemical toxicity took on increasing and great importance over the past 100 years: How can we determine whether certain exposures are or are not harmful to human health? Assuming there are no bright lines between harmful (unsafe) and harmless (safe) exposures, how do we make decisions that will be health protective? Why and how did risk and its assessment enter the discussion? Why did they become important and why has there been such a struggle over them? 3 4 U.S. National Academy of Sciences 1983 The Red Book What led to the report? What did the report really say? Why was it important? The Silver Book 25 years of additional studies and applications captured in 2008 report (Science and Decisions) 5 All Substances are Poisons The right dose differentiates a poison and a remedy. Paracelsus 16 th century, Swiss For chemicals that are not remedies, The right dose differentiates we would rewrite: a poison from a non-poison. Thus arises the concept of: THRESHOLDS FOR TOXICITY How do we identify thresholds for large, diverse populations? 6

2 Dr. Alice Hamilton ( ) Earliest US Law Pertaining to Chemical Toxicity Pioneering work in occupational medicine when Rachel Carson was in her childhood and youth. Investigated and called to national attention the plight of workers exposed to lead, benzene, and other hazardous substances. The need to prevent occupational illness was an early incentive for learning about toxicity through animal studies s-1910 Federal Law Social, Political Activism 1906 Pure Food & Drug Act Foods & drugs shall not contain adulterants that may cause harm Regulatory Enforcement Bureau of Chemistry, USDA (Harvey Wiley) Burden of showing adulteration on government Wiley s Poison Squad begins to assess safety 1916 Supreme Court: animal data sufficient to show a substance may cause harm 8 Other Pre-Silent Spring Events Forcing Attention on Chemical Safety Contrary to Nature : Galen, 2nd Century, on Cancers EVENTS ( ) Increasing concerns about occupational diseases Increasing numbers of chemicals in commerce, with growth accelerating after WWII RESPONSES ACGIH/TLV s: 1940s Expert judgment used to develop occupational exposure limits New laws pertaining to food additives, contaminants, pesticide residues New safety requirements:1950s Increasing dependence on animal studies Galen thought cancers were due to imbalances in the bodily humors 16 centuries later, evidence began to develop that Galen was incorrect. Recognition of air and water pollution as major public health concerns Public health authorities develop recommended exposure limits for a few substances No clearly identifiable relationships between those limits and toxicity data 9 10 Contrary to Nature : Galen, 2nd Century, on Cancers By the 1950s: Prevailing View in Public Health Communities Percivall Pott Observations of excessive numbers of scrotal cancers among London s chimney sweeps Resulted from an external source: soot Other environmental causes of cancer identified (coal tars, other sources of soot, arsenicals, dyes) First experimental induction of cancers Japan th century E. L. Kennaway (London) identifies PAH s as cancer-causing compounds in soots By the 1940s-1950s many scientists had singled out carcinogens for special treatment. They were especially dangerous at very low doses. They mimicked ionizing radiation. Chemicals induced toxicities through biological mechanisms involving thresholds. Toxicity-free levels must exist Carcinogens were the exception to this rule. No safe levels can be identified All the food-related laws enacted during the 1950s included Congressman Delaney s clause, strictly forbidding the addition to food, in any amount, of chemicals shown to induce cancers in humans OR animals

3 Arnold Lehman & O. Garth Fitzhugh (FDA, 1950s) ADI Derivation ADI: the Allowable Daily Intake Published the method that would be followed to establish safe levels of human intake for chemicals introduced into food. As long as human exposures to a chemical did not exceed the ADI, the legal requirement of practical certainty of no harm would be satisfied. No ADI would be established for any chemical that caused cancer. This use of the ADI and the zero-tolerance for carcinogens were consistent with new food law requirements. Starting point: animal toxicity data or epidemiology data Identify highest dose exhibiting no toxic-effect (NOAEL) NOAEL is threshold dose for the group studied. But for a large, diverse human population: 1Average human assumed to be 10x more sensitive than experimental animals. 2Threshold doses should vary in human population (10x). ADI = NOAEL 10x10 Lehman Fitzhugh called the divisors Safety Factors What Does the ADI Tell Us? The Situation for Regulators in the 1970s Only that exposures at and below it are probably not very risky. The ADI and its equivalent measures** are not Risk measures No information is provided regarding the probability of a toxic response at the ADI. ADI s and RfD s are not truly bright lines between safe and unsafe exposures, yet typically applied as if they were. ** What EPA came to call toxicity Reference Doses (RfD s) and Reference Concentrations (RfC s) AVOIDABLE CHEMICAL EXPOSURES Substances intentionally added to foods and other products Addition can simply be halted if safety is in question. The ADI or RfD or RfC readily function as safety criteria. The zero tolerance approach can be applied if any such chemical is found to be a carcinogen. UNAVOIDABLE CHEMICAL EXPOSURES Substances that have become contaminants of the environment Exposures can be reduced but not easily eliminated. Exposures can perhaps be forced to levels below ADI s or RfD s or RfC s, but often technologies necessary to achieve such a goal are either not available or exceedingly costly. Exposures to carcinogens can be reduced, but there is no way to determine whether any particular reduction achieves adequate health protection Carcinogen Risk BENZENE VINYL CHLORIDE The problem could no longer be ignored. EPA and FDA began adopting methods to estimate low-dose cancer risks. The no-threshold assumption was adopted. A linear dose-response model was adopted. Upper bounds on low-dose cancer risk were developed. Carcinogens would be regulated based on risk. OSHA rejected such an approach in 1979 in its proposal to regulate workplace exposures to benzene. The Supreme Court overturned OSHA s interpretation of the law and determined that a risk-based approach had to be used. AFLATOXIN Regulatory Applications of Cancer Risk Assessments Began to take on these forms during the late 1970s/early 1980s and remain in place today! AVOIDABLE EXPOSURES Risk had to fall below a de minimis level* (too small to be of consequence). UNAVOIDABLE EXPOSURES Applications of different approaches to exposure control would lead to different degrees of risk reduction (health benefit) at different costs. This approach allowed distinctions to be made among the cost-effectiveness of different approaches to regulation. Risks remaining after regulation must be sufficiently small to ensure a large degree of health protection, but do not need to reach de minimis levels. DIMETHYLNITROSAMINES DES ASBESTOS PAHs 17 *Except where Delaney Clause applies. 18

4 Controversies Mid 1970s to Early 1980s Risk Assessment The saccharin disaster 1976 Quantification of cancer risk Too many untestable assumptions! Too risky! Overly cautious! Risk assessments manipulated by regulatory scientists to achieve desired outcomes. U.S. Congress persuaded to call for a National Academy study. The Red Book was the result. RISK ASSESSMENT: A standardized framework within which research information is organized, evaluated, and put into a form useful for decisions about threats to health, safety, environment. National Academy of Sciences, 1983 Risk Assessment in the Federal Government: Managing the Process Risk Analysis The Problem RESEARCH Toxic or other hazardous properties of environmental agents* Human and environmental exposures *Agents can be chemical, biological, physical. RISK ASSESSMENT RISK COMMUNICATION RISK MANAGEMENT Decisions to protect health, environment Restrictions on exposures Warnings Education Required technical controls *Driven by legal requirements and generally recognized standards of care. 1 Data collected about the hazards of specific agents: epidemiological/experimental BUT: 1 What can be said about the probability that the hazardous properties of those agents will be expressed in: other populations exposed under other conditions? Requires extrapolation beyond data The Red Book Solution: Explicit Guidelines Essential Science What is the most reliable evidence concerning hazard, dose-risk relationships, and exposure? What evidence will be used for risk assessment? How will uncertainties be dealt with? *THE DEFAULTS Under what circumstances can one or more of the selected options be replaced by scientific data? (Unavoidable) inferences beyond the science What options are available to deal with the great unknowns of: Interindividual Variability Interspecies Variability Low-Dose risks? What options are available to deal with the unknowns in exposure assessment? What options will be selected for general use in risk assessment?* 23 Risk Assessment Regulators develop guidelines Several National Academies studies further emphasize the importance of risk assessment and the soundness of Red Book Many scientific refinements and new applications Unending controversy and criticism Uncertainties ignored Defaults overshadow science Many applications inadequate/incomplete Decision framework lacking Non-cancer risks not quantified Pace of risk assessments insufficient to meet societal demands Adequate Risk Communication becomes essential 24

5 Science & Decisions Silver Book Calls for Unification Approach to Dose-Response Assessment Risk assessment is at a crossroads, and its credibility is being challenged. Science is increasingly complex. Risk assessment is being extended to address broader environmental questions, such as life-cycle analysis and issues of costs, benefits, and risk-risk tradeoffs. Stakeholders are often disengaged from the risk-assessment process at a time when risk assessment is increasingly intertwined with societal concerns. Disconnects between the available scientific data and the information needs of decision makers hinder the use of risk assessment as a decision-making tool. The Silver Book, 2008, National Academy Dose-response assessments are now conducted differently for cancer and noncancer effects. Methods have been criticized for not providing the most useful results, and for not reflecting current scientific understanding. A consistent approach to risk assessment for cancer and noncancer effects is scientifically feasible and must be implemented Unification of Dose-Response Assessment Where Are We Now? Move toward quantification of population risk for all health end points? It will happen only if regulators make it happen. Scientific debate about toxic hazards and their risks to health will continue. Advocacy for hazard-based regulation remains strong. Biologically based models are making inroads, replacing defaults, but movement is slow. New types of health concerns and unusual dose-response relationships have increasing attention. Applications in life-cycle assessment and complex, multi-stressor environmental contexts are increasing. Public concerns about chemical risks will remain high An Optimistic View of What Remains? The Next 50 Years? Public Understanding of These Matters is Poor Research on the biological events underlying the induction of toxicity reveal much greater understanding of low-dose effects and population variability. Very high-throughput toxicity testing based on computation and suites of in vitro assays will gradually replace animal testing. Huge amounts of data from high-throughput testing will have to be evaluated using new, rapid approaches to risk assessment. The new toxicity and risk assessment tools will allow us to evaluate virtually all of the many thousands of chemicals in commerce and all of the environmental contaminants. Creating that understanding is especially problematic for risks to health that are: Largely involuntary Subject to much scientific disagreement Low probability, high consequence Not perceived as offset by personal benefit Industrial in origin Public education on these matters is absent

6 Perhaps the Most Important Legacy of Silent Spring: The Right to Know Rachel Carson told us that We urgently need an end to... false assurances, to the sugar coating of unpalatable facts....the public must decide whether it wishes to continue on the present road, and it can do so only when in full possession of the facts. In the words of Jean Rostand, The obligation to endure gives us the right to know. Rachel Carson was a highly effective communicator about risk. The movement toward thoroughly transparent and science-based decisions about risk, now clearly demanded by the public, could be said to have begun with Rachel Carson's powerful message. 31