Changing the Risk Paradigms Can be Good for Our Health: J-Shaped, Linear and Threshold Dose-Response Models.

Both the linear (at low doses)-no-threshold (LNT) and the threshold models (S-shapes) dose-response lead to no benefit from low exposure. We propose three new models that allow and include, but do not require - unlike LNT and S-shaped models - this strong assumption. We also provide the means to calculate benefits associated with bi-phasic biological behaviors, when they occur and propose:THREE HORMETIC (PHASIC) MODELS: the J-shaped, inverse J-shaped, the min-max, andMethod for calculating the direct benefits associated with the J and inverse J-shaped models.The J-shaped and min-max models for mutagens and carcinogenic agents include an experimentally justified repair stage for toxic and carcinogenic damage. We link these to stochastic transition models for cancer and show how abrupt transitions in cancer hazard rates, as functions of exposure concentrations and durations, can emerge naturally in large cell populations even when the rates of cell-level events increase smoothly (e.g., proportionally) with concentration. In this very general family of models, J-shaped dose-response curves emerge. These results are universal, i.e., independent of specific biological details represented by the stochastic transition networks. Thus, using them suggests a more complete and realistic way to assess risks at low doses or dose-rates.

The protection of wildlife from mortality: hypothesis and results for risk assessment.

Wildlife deaths associated with cyanide-bearing tailings dams are a significant environmental issue that has affected the gold mining industries for many years and still characterized by little knowledge about how to measure, monitoring, reduce or eliminate those deaths. The purpose of this paper is statistically to determine: the potential for establishing causal relations between exposure to cyanide (in its most common species relevant to tailings) and response (measured by death counts), to develop a protocol of data analysis, the understanding of the significance of data gaps, and the effect of likely risk management interventions to achieve the goals of the International Cyanide Management Code (ICMC); [ICMC The International Cyanide Management Institute. International cyanide management code, the international cyanide management institute 2005, www.cyanidecode.org.]. However, operator's certification under the ICMC is difficult because of the limited data and potentially serious under-estimation of the death counts. This is due to observational skill and monitoring frequency, the small size of the carcasses, large extent of tailings facilities, carcasses loss by; entombment in tailings, sink, or taken by scavenging wildlife. This (1st order or bounding) assessment results focus on bird-deaths, which appear to be most frequent at sites where elevated cyanide concentrations are found. Those results indicate that the empirical causal associations we generate support the hypotheses that: This paper also develops the basis for a complete risk assessment study to be based on additional data gathering activities and detailed statistical analyses. These two activities, combined with a risk management plan also being developed, will provide a tool for compliance with the ICMC.

Hormesis and precaution: the twain shall meet.

Regulatory focus on quantifying risk of disease or death from exposure to hazardous substances via monotonic dose-response models has downplayed or even rejected potential benefits to human health from exposures to low (sub-threshold) doses, and thus represented by either U-shaped or J-shaped models. On the other hand, most environmental health policy hypothesizes, without firm evidence, that cancer risk is proportional to exposure at low doses of current ambient exposures. An acceptable exposure is determined by either setting a somewhat arbitrary ;acceptable' level of risk, such as one in a million excess individual lifetime cancer risk or, in the case of several types of animal toxicological test results, applying multiplicative safety factors to a specific concentration, generally derived from a benchmark dose or NOAEL. This seemingly precautionary approach is questionable in light of much experimental evidence indicating protective effects of exposure at low doses - U-shaped or J-shaped models. We demonstrate that incorporating the possibility of hormesis into regulatory decision-making is precautionary, while use of default results in policy conflicts with precaution.

A critical review of the effects of gold cyanide-bearing tailings solutions on wildlife.

Wildlife deaths associated with cyanide-bearing mine waste solutions have plagued the gold mining industries for many years, yet there is little published data showing the relationship between wildlife mortality and cyanide toxicity. A gap of knowledge exists in monitoring, understanding the causal relationships and managing risks to wildlife from cyanide-bearing waste solutions and tailings. There is a need for the gold industry to address this issue and to meet the International Cyanide Management Code (ICMC) guidelines. The perceived extent of the issue varies, with one study finding the issue inadequately monitored and wildlife deaths grossly underestimated. In Nevada, USA during 1990 and 1991, 9512 carcasses were reported of over 100 species, although there was underestimation due to reporting being voluntary. Of these, birds comprised 80-91% of vertebrate carcasses reported annually. At Northparkes, Australia in 1995, it was initially estimated that 100 bird carcasses were present by mine staff following a tailings incident; when a thorough count was conducted, 1583 bird carcasses were recorded. Eventually, 2700 bird deaths were documented over a four-month period. It is identified that avian deaths are usually undetected and significantly underestimated, leading to a perception that a risk does not exist. Few guidelines and information are available to manage the risks of cyanide to wildlife, although detoxification, habitat modification and denying wildlife access have been used effectively. Hazing techniques have proven ineffective. Apparently no literature exists that documents accurate wildlife monitoring protocols on potentially toxic cyanide-bearing mine waste solutions or any understanding on the analysis of any derived dataset. This places the onus on mining operations to document that no risk to wildlife exists. Cyanide-bearing tailings storage facilities are environmental control structures to contain tailings, a standard practice in the mining industry. Cyanide concentrations below 50 mg/L weak-acid-dissociable (WAD) are deemed safe to wildlife but are considered an interim benchmark for discharge into tailings storage facilities (TSFs). Cyanide is a fast acting poison, and its toxicity is related to the types of cyanide complexes that are present. Cyanide in biota binds to iron, copper and sulfur-containing enzymes and proteins required for oxygen transportation to cells. The accurate determination of cyanide concentrations in the field is difficult to achieve due to sampling techniques and analytical error associated with loss and interferences following collection. The main WAD cyanide complexes in gold mine tailings are stable in the TSF environment but can release cyanide ions under varying environmental conditions including ingestion and absorption by wildlife. Therefore distinction between free, WAD and total cyanide forms in tailings water for regulatory purposes is justified. From an environmental perspective, there is a distinction between ore bodies on the basis of their copper content. For example, wildlife deaths are more likely to occur at mines possessing copper-gold ores due to the formation of copper-cyanide complexes which is toxic to birds and bats. The formation of copper-cyanide complex occurs preferentially to gold cyanide complex indicating the relative importance of economic vs. environmental considerations in the tailings water. Management of cyanide to a perceived threshold has inherent risks since cyanide has a steep toxicity response curve; is difficult to accurately measure in the field; and is likely to vary due to variable copper content of ore bodies and ore blending. Consequently, wildlife interaction needs to be limited to further reduce the risks. A gap in knowledge exists to design or manage cyanide-bearing mine waste solutions to render such facilities unattractive to at-risk wildlife species. This gap may be overcome by understanding the wildlife behaviour and habitat usage of cyanide-bearing solutions.

Science-policy in environmental and health risk assessment: if we cannot do without, can we do better?

How can empirical evidence of adverse effects from exposure to noxious agents, which is often incomplete and uncertain, be used most appropriately to protect human health? We examine several important questions on the best uses of empirical evidence in regulatory risk management decision-making raised by the US Environmental Protection Agency (EPA)'s science-policy concerning uncertainty and variability in human health risk assessment. In our view, the US EPA (and other agencies that have adopted similar views of risk management) can often improve decision-making by decreasing reliance on default values and assumptions, particularly when causation is uncertain. This can be achieved by more fully exploiting decision-theoretic methods and criteria that explicitly account for uncertain, possibly conflicting scientific beliefs and that can be fully studied by advocates and adversaries of a policy choice, in administrative decision-making involving risk assessment. The substitution of decision-theoretic frameworks for default assumption-driven policies also allows stakeholder attitudes toward risk to be incorporated into policy debates, so that the public and risk managers can more explicitly identify the roles of risk-aversion or other attitudes toward risk and uncertainty in policy recommendations. Decision theory provides a sound scientific way explicitly to account for new knowledge and its effects on eventual policy choices. Although these improvements can complicate regulatory analyses, simplifying default assumptions can create substantial costs to society and can prematurely cut off consideration of new scientific insights (e.g., possible beneficial health effects from exposure to sufficiently low 'hormetic' doses of some agents). In many cases, the administrative burden of applying decision-analytic methods is likely to be more than offset by improved effectiveness of regulations in achieving desired goals. Because many foreign jurisdictions adopt US EPA reasoning and methods of risk analysis, it may be especially valuable to incorporate decision-theoretic principles that transcend local differences among jurisdictions.

Causation in risk assessment and management: models, inference, biases, and a microbial risk-benefit case study.

Causal inference of exposure-response relations from data is a challenging aspect of risk assessment with important implications for public and private risk management. Such inference, which is fundamentally empirical and based on exposure (or dose)-response models, seldom arises from a single set of data; rather, it requires integrating heterogeneous information from diverse sources and disciplines including epidemiology, toxicology, and cell and molecular biology. The causal aspects we discuss focus on these three aspects: drawing sound inferences about causal relations from one or more observational studies; addressing and resolving biases that can affect a single multivariate empirical exposure-response study; and applying the results from these considerations to the microbiological risk management of human health risks and benefits of a ban on antibiotic use in animals, in the context of banning enrofloxacin or macrolides, antibiotics used against bacterial illnesses in poultry, and the effects of such bans on changing the risk of human food-borne campylobacteriosis infections. The purposes of this paper are to describe novel causal methods for assessing empirical causation and inference; exemplify how to deal with biases that routinely arise in multivariate exposure- or dose-response modeling; and provide a simplified discussion of a case study of causal inference using microbial risk analysis as an example. The case study supports the conclusion that the human health benefits from a ban are unlikely to be greater than the excess human health risks that it could create, even when accounting for uncertainty. We conclude that quantitative causal analysis of risks is a preferable to qualitative assessments because it does not involve unjustified loss of information and is sound under the inferential use of risk results by management.

Investigation of a cluster of leukaemia in the Illawarra region of New South Wales, 1989-1996.

OBJECTIVES: To investigate a cluster of leukaemia among young people and assess the plausibility of a disease-exposure relationship. DESIGN: Descriptive analysis of population-based leukaemia incidence data, review of evidence related to the causation of leukaemia, assessment of environmental exposures to known leukaemogens, and resulting risks of leukaemia. SETTING: Illawarra region of New South Wales, Australia, focusing on suburbs between the Port Kembla industrial complex and Lake Illawarra (the Warrawong area). MAIN OUTCOME MEASURES: Standardised incidence ratios (SIRs) for leukaemia; current measured and past estimated ambient air benzene concentrations; and expected leukaemia cases attributable to estimates of ambient air benzene concentrations. RESULTS: In 1989-1996, 12 leukaemia cases among Warrawong residents aged less than 50 years were observed, more than the 3.49 cases expected from the rate in the rest of the Illawarra region (SIR, 343.8; 99% CI, 141.6-691.7). These people lived in suburbs immediately to the south-southwest of a coke byproducts plant (a major industrial source of benzene, one of the few known leukaemogens). The greatest excess was among 15-24-year-olds (SIR, 1085.6; 99% CI, 234.1-3072.4). In 1996, ambient air concentrations of benzene averaged less than 1 part per billion (ppb). Since 1970, ambient air concentrations of benzene were estimated to have averaged up to 3 ppb, about one-thousandth of the level at which leukaemia risk has been identified in occupational epidemiological studies. Using the risk assessment model developed by the US Environmental Protection Agency, we estimate that past benzene levels in the Warrawong area could have resulted in 0.4 additional cases of leukaemia in 1989-1996. CONCLUSIONS: The excess occurrence of leukaemia in the Warrawong area in 1989-1996 is highly unusual. Current environmental benzene exposure and the reconstructed past environmental benzene exposure level are too low to explain the large excess of leukaemia. The cause of the cluster is uncertain.

Reassessing benzene cancer risks using internal doses.

Human cancer risks from benzene exposure have previously been estimated by regulatory agencies based primarily on epidemiological data, with supporting evidence provided by animal bioassay data. This paper reexamines the animal-based risk assessments for benzene using physiologically-based pharmacokinetic (PBPK) models of benzene metabolism in animals and humans. It demonstrates that internal doses (interpreted as total benzene metabolites formed) from oral gavage experiments in mice are well predicted by a PBPK model developed by Travis et al. Both the data and the model outputs can also be accurately described by the simple nonlinear regression model total metabolites = 76.4x/(80.75 + x), where x = administered dose in mg/kg/day. Thus, PBPK modeling validates the use of such nonlinear regression models, previously used by Bailer and Hoel. An important finding is that refitting the linearized multistage (LMS) model family to internal doses and observed responses changes the maximum-likelihood estimate (MLE) dose-response curve for mice from linear-quadratic to cubic, leading to low-dose risk estimates smaller than in previous risk assessments. This is consistent with the conclusion for mice from the Bailer and Hoel analysis. An innovation in this paper is estimation of internal doses for humans based on a PBPK model (and the regression model approximating it) rather than on interspecies dose conversions. Estimates of human risks at low doses are reduced by the use of internal dose estimates when the estimates are obtained from a PBPK model, in contrast to Bailer and Hoel's findings based on interspecies dose conversion. Sensitivity analyses and comparisons with epidemiological data and risk models suggest that our finding of a nonlinear MLE dose-response curve at low doses is robust to changes in assumptions and more consistent with epidemiological data than earlier risk models.

Acceptable cancer risks: probabilities and beyond.

The acceptability of cancer risk requires consideration of factors that extend beyond mere numerical representations, such as either individual lifetime risk in excess of background and excess incidence. Recently, use of these numbers has been tempered by the addition of qualitative weights-of-evidence that describe the degree of support provided by animal and epidemiologic results. Nevertheless, many other factors, most of which are not quantitative, require incorporation but remain neglected by the analyst eager to use quantitative results. In this paper we show that simple risk measures are often fraught with problems. Moreover, these measures do not incorporate the very essence of acceptability, which includes notions of responsibility, accountability, equity, and procedural legitimacy, among others. We link the process of risk assessment to those legal and regulatory standards that shape it. These standards are among the principal means to resolve risk-related disputes and to enhance the balancing of competing interests when science and law meet on uncertain and often conjectural ground. We conclude the paper with a proposal for the portfolio approach to manage cancer risks and to deal with uncertain scientific information. This approach leads to the concept of "provisional acceptability," which reflects the choices available to the decisionmaker, and the trade-offs inherent to such choices.

Risk and benefit in environmental law.

Judicial review establishes whether the mandate of Congress is observed by an agency's rule-making mechanisms for setting environmental standards or other regulations. Central issues in risk assessment now include whether a risk is significant, what the burden of proof for significance is, how to resolve the tension between the effort to reduce hazardous exposures and the goal of efficient regulation, and precisely how and in what detail the costs of regulation must be measured. Under current regulatory statutes, there are several paradigms for balancing costs and benefits.