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The concept that "safe levels of exposure" for humans can be identified for individual chemicals is central to the risk assessment of compounds with known toxicological profiles. The Threshold of Toxicological Concern (TTC) is a concept that refers to the establishment of a level of exposure for all chemicals, whether or not there are chemical-specific toxicity data, below which there would be no appreciable risk to human health. The concept proposes that a low level of exposure with a negligible risk can be identified for many chemicals, including those of unknown toxicity, based on knowledge of their chemical structures. The present paper aims to describe the history of the TTC principle, its use to date, its potential future applications and the incorporation of the TTC principle in the Risk Assessment paradigm.

Despite major advances in the diagnosis and treatment of atherosclerotic cardiovascular disease (CVD) in the past century, it remains a serious clinical and public health problem. Multivariable risk factor analysis is now commonly performed to identify high-risk candidates for CVD who need preventive measures and to seek out clues to the pathogenesis of the disease. The set of risk factors used for the former is constrained by practical considerations, and the set of risk factors used for the latter is constrained by the hypothesis being tested. This report reviews the evolution and usefulness of multivariable risk functions crafted for estimating risk of clinical manifestations of atherosclerosis and for gaining insights into their pathogenesis. Decades of evaluation of CVD risk factors by the Framingham Study led to the conclusion that CVD risk evaluation is most fruitfully appraised from the multivariable risk posed by a set of established risk factors. Such assessment is essential because risk factors seldom occur in isolation, and the risk associated with each varies widely depending on the burden of associated risk factors. About half the CVD in the general population arises from the segment with multiple marginal risk factor abnormalities. Although disease-specific profiles are available, a multivariable risk formulation for coronary disease comprised of age, sex, the total/high-density lipoprotein cholesterol ratio, systolic blood pressure, glucose intolerance, cigarette smoking, and electrocardiography-left ventricular hypertrophy is also predictive of peripheral artery disease, heart failure, and stroke because of shared risk factors. Correcting risk factors for any particular CVD has the potential to protect against > or =1 of the others. Multivariable risk stratification is now recognized as essential in efficiently identifying likely candidates for CVD and quantifying the hazard.

This article begins with a review of the regulation of chemicals in Sweden over the past 30 years, focusing particularly on the 1997 Government Environmental Quality Bill, which called for a toxic-free society by the year 2020. The second part of the article analyzes why Sweden has taken this route. The third and final section discusses Sweden's present role in formulating present EU chemical regulation, such as the recent EU Chemical White Paper, and hypothesizes future impacts of Swedish chemical regulations on the EU itself.

The science of toxicology has served society well in protecting public health and the environment. Governments, the industrial sector, and the public have relied on toxicology as the foundation to assess risks to both human and ecological populations from environmental factors, including chemicals, biologic agents, physical agents, and other stressors. To maintain its prominence, the science and practice of toxicology will need to embrace the revolution underway in biology. Systems biology and biotechnologies derived from sequencing of the human genome, referred to as "genomics," have created exciting possibilities for application to human health and environmental risk assessment. Yet this rapid advance of science and technology can be overshadowed by inconsistency in study design and sampling strategies; by the lack of quantitative or qualitative correlations of exposure, dose, or adverse effects; and by the lack of bioinformatics tools and analytical methods necessary to manage the volume of research findings. These limitations may render results uninterpretable and difficult, if not impossible, to use in risk assessment. Recommendations will be discussed to improve integrating systems biology and genomics into risk assessment so that the inherent promise of these new approaches can be realized.

In the spring of 1993, nearly 40 percent of Milwaukee-area residents experienced a nationally publicized outbreak of cryptosporidium, a parasite that infested the metropolitan drinking water supply. Using open-ended survey data gathered from 610 adult residents in the wake of that outbreak, this study looks at factors related to the ways in which people make sense of their quantitative personal risk estimates. The concepts of informal reasoning and attribution aided this endeavor. Analysis of open-ended comments about the risk of getting ill from a waterborne parasite indicated that explanations of personal risk were consistent with predictions made by attribution theory. Good outcomes, which included having remained healthy during the outbreak, were associated with a greater likelihood that respondents would attribute causation to themselves, while one specific bad outcome, having experienced the illness, was associated with a greater likelihood that respondents would attribute causation externally. This study also examined predictors of whether respondents employed probabilistic language in those attributions. Analysis indicated that income was positively related to the use of probability-oriented language, while age and race were negatively related to the use of such language (i.e., persons of color and older individuals were less likely to use such language).

This paper examines international standard-setting in the toxicology of pharmaceuticals during the 1990s, which has involved both the pharmaceutical industry and regulatory agencies in an organization known as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The analysis shows that the relationships between innovation, regulatory science and 'progress' may be more complex and controversial than is often assumed. An assessment of the ICH's claims about the implications of 'technical' harmonization of drug-testing standards for the maintenance of drug safety, via toxicological testing, and the delivery of therapeutic progress, via innovation, is presented. By demonstrating that there is not a technoscientific validity for these claims, it is argued that, within the ICH, a discourse of technological innovation and scientific progress has been used by regulatory agencies and prominent parts of the transnational pharmaceutical industry to legitimize the lowering and loosening of toxicological standards for drug testing. The mobilization and acceptance of this discourse are shown to be pivotal to the ICH's transformation of reductions in safety standards, which are apparently against the interests of patients and public health, into supposed therapeutic benefits derived from promises of greater access to more innovative drug products. The evidence suggests that it is highly implausible that these reductions in the standards of regulatory toxicology are consistent with therapeutic progress for patients, and highlights a worrying aspect embedded in the 'technical trajectories' of regulatory science.

The fugacity model for evaluating DDTs dynamic performances in the environment was combined with the dietary exposure evaluation model, including the contribution of imported food, to develop the macroscopic mathematical model relating DDTs in the environment with the health risks of the reference Japanese. The model validity was examined by comparing the simulated DDTs concentrations in environmental media, various kinds of food, and dietary intake with those observed. Numerical simulations were done for the past half and future of one century to evaluate the effect of the DDTs usage prohibition in 1970 in Japan. The major results obtained under the limits considered are as follows. The DDTs concentrations in environmental media, various kinds of foods, and the dietary intake showed the steady exponential decrease after the DDTs usage prohibition in 1970. The DDE/DDTs ratio is larger in the higher position in an ecological system, and increased steadily with time. The critical exposure of DDTs occurred through animal product intake until 1960; after 1990 marine product intake caused the most exposure. The estimated DDTs intake was evaluated to be less than the PTDI and RfD. The annual excess cancer induction risk due to the annual dietary intake of DDTs was the largest at the level of (0.5 - 2.0) x 10(-6) (1/yr) in the early 1970s. The effect of the DDT usage prohibition on dietary exposure reduction was expected to appear after about 20 years. The life-span excess cancer induction risk was conservatively estimated to be larger than 10(-5) (1/lifespan) for the reference Japanese who were born before 1970. The DDTs usage prohibition in 1970 was effective to reduce the life-span cancer risk under the 10(-5) level.

After a brief overview of the contributions of Paracelsus, Haber and Arndt to the theory of toxicology, examples are provided for quantitative risk/safety assessments using dose (c), time (t) and effect (E) as macroscopic variables of toxicity. The discussion offers explanations for application of the decision tree approach in identifying rate-determining steps in the toxicity of chemicals. Having done so allows for reasonably accurate predictions of cancer incidence (bladder, liver, heart, histiocyte) using Haber's Product under isoeffective conditions and the equation cxt=kxE for isodosic and isotemporal responses.

As a result of routine monitoring data on carrots generated in the 1990s indicating MRL exceedances, further studies showed that residues of organophosphorus compounds in individual roots could vary up to 25 times the levels found in composite samples. Additional work found that this phenomenon also extended to other crops including apples, peaches and celery. Variability (defined as the highest residue level found in any one crop item divided by the level found in a composite sample from the same batch) of up to 34 times mean values was found in one batch of plums. Conventional deterministic methods used in consumer assessments were likely to give gross overestimates of short-term exposure because of the assumptions employed. This led to the development of probabilistic models which made the best use of all available information and was capable of indicating percentages of consumers that could exceed relevant toxicological end points. This indicated that there was unlikely to be serious health effects as a result of ingesting these residues and has subsequently proved to be a useful aid to regulatory decision making.

This paper deals with the social construction of medical success in various therapies used to treat tuberculosis during the first half of the 20th Century. The three main therapies discussed-Tuberculin treatment, sanatorium therapy and chest surgery-show distinctly different success patterns. For example, the success of sanatorium treatment was evaluated differently during and after treatment: during treatment, quantifiable data such as weight and body temperature were seen as indicators of health. After discharge, however, success was defined as long-term survival. On the other hand, when chest surgery was used, success meant simply that patient was able to survive the surgery itself-long-term effects and patient's survival after discharge were not addressed. Such comparisons illustrate that the definition of medical success rested as much on the dismissal of negative data as on positive empirical results.

This article describes the evolution of the process for assessing the hazards of a geologic disposal system for radioactive waste and, similarly, nuclear power reactors, and the relationship of this process with other assessments of risk, particularly assessments of hazards from manufactured carcinogenic chemicals during use and disposal. This perspective reviews the common history of scientific concepts for risk assessment developed until the 1950s. Computational tools and techniques developed in the late 1950s and early 1960s to analyze the reliability of nuclear weapon delivery systems were adopted in the early 1970s for probabilistic risk assessment of nuclear power reactors, a technology for which behavior was unknown. In turn, these analyses became an important foundation for performance assessment of nuclear waste disposal in the late 1970s. The evaluation of risk to human health and the environment from chemical hazards is built on methods for assessing the dose response of radionuclides in the 1950s. Despite a shared background, however, societal events, often in the form of legislation, have affected the development path for risk assessment for human health, producing dissimilarities between these risk assessments and those for nuclear facilities. An important difference is the regulator's interest in accounting for uncertainty.