A framework for fit-for-purpose dose response assessment

The NRC report Science and Decisions: Advancing Risk Assessment made several recommendations to improve chemical risk assessment, with a focus on in-depth chronic dose–response assessments conducted by the U.S. Environmental Protection Agency. The recommendations addressed two broad elements: improving technical analysis and utility for decision making. To advance the discussions in the NRC report, in three multi-stakeholder workshops organized by the Alliance for Risk Assessment, available and evolving risk assessment methodologies were considered through the development and application of case studies. A key product was a framework (http://www.allianceforrisk.org/Workshop/Framework/ProblemFormulation.html) to guide risk assessors and managers to various dose–response assessment methods relevant to a range of decision contexts ranging from priority setting to full assessment, as illustrated by case studies. It is designed to facilitate selection of appropriate methodology for a variety of problem formulations and includes a variety of methods with supporting case studies, for areas flagged specifically by the NRC committee for consideration – e.g., susceptible sub-populations, population variability and background. The framewok contributes to organization and communication about methodologies for incorporating increasingly biologically informed and chemical specific knowledge into dose–response analysis, which is considered critical in evolving fit-for-purpose assessment to address relevant problem formulations.     

Accelerating the development of 21st-century toxicology: outcome of a Human Toxicology Project Consortium workshop

The U.S. National Research Council (NRC) report on "Toxicity Testing in the 21st century" calls for a fundamental shift in the way that chemicals are tested for human health effects and evaluated in risk assessments. The new approach would move toward in vitro methods, typically using human cells in a high-throughput context. The in vitro methods would be designed to detect significant perturbations to "toxicity pathways," i.e., key biological pathways that, when sufficiently perturbed, lead to adverse health outcomes. To explore progress on the report's implementation, the Human Toxicology Project Consortium hosted a workshop on 9-10 November 2010 in Washington, DC. The Consortium is a coalition of several corporations, a research institute, and a non-governmental organization dedicated to accelerating the implementation of 21st-century Toxicology as aligned with the NRC vision. The goal of the workshop was to identify practical and scientific ways to accelerate implementation of the NRC vision. The workshop format consisted of plenary presentations, breakout group discussions, and concluding commentaries. The program faculty was drawn from industry, academia, government, and public interest organizations. Most presentations summarized ongoing efforts to modernize toxicology testing and approaches, each with some overlap with the NRC vision. In light of these efforts, the workshop identified recommendations for accelerating implementation of the NRC vision, including greater strategic coordination and planning across projects (facilitated by a steering group), the development of projects that test the proof of concept for implementation of the NRC vision, and greater outreach and communication across stakeholder communities.     

The calculation and use of carcinogenic potency: A review

Six methods of estimating carcinogenic potency now in use to some extent by regulatory agencies are examined. It is concluded that none of these methods is adequate for regulatory decision making when used alone, as is usually the case, but that all are useful as a contribution to the whole risk assessment process. The needs for further development and improvement of these methods, where appropriate to human risk, are identified and discussed in view of the growing use of potency estimates in regulatory decision making.     

Workshop report: identifying key issues underpinning the selection of linear or non-linear dose-response extrapolation for human health risk assessment of systemic toxicants

The report of an Expert Panel convened by the National Research Council (NRC) of the National Academy of Sciences (NAS), entitled Science and Decisions: Advancing Risk Assessment (National Research Council, 2009a), includes a recommendation to use, as a default approach, low-dose linear extrapolation for systemic toxicity. This recommendation represents a significant departure from long-standing risk assessment practices for non-cancer toxicity, where the most appropriate No Observed Adverse Effect Level (NOAEL) or Benchmark Dose (BMD) of the critical effect in the key study is selected, and then a "safe exposure" level is derived by applying uncertainty factors to account for dataset completeness, potential greater sensitivity of humans when compared with experimental animals, and for potential variability of sensitivity in humans. A workshop was held to "frame" issues raised by the NAS report that needed further study. Workshop objectives included the following: (1) identify the issues raised by the 2009 NRC report and discuss the extent to which existing science may (or may not) align with the NAS analyses and recommendations, and (2) identify/develop possible actions to assist in advancing deeper and broader considerations of some of the critical issues presented by the 2009 NAS Panel. Experts invited to this "Framing" Workshop encompassed a full spectrum of toxicology and risk assessment disciplines; in particular, expertise in molecular interactions and dose-response of biological systems were well represented. The recommendations developed at this Framing Workshop provide specific ideas on possible further steps to facilitate deeper and broader consideration of the issues underpinning dose-response extrapolation in the risk assessment of systemic toxicants.     

Drinking water standards and risk assessment

The role and use of risk assessment methods in the establishment of drinking water standards are described with emphasis on recent applications. The process essentially includes an attempt to quantify human exposure from all routes including drinking water, animal toxicology, and human epidemiology, when available, to arrive at drinking water concentrations at which exposure would result in "no known or anticipated adverse effects on health, with a margin of safety." The process itself is straightforward; however, the application to decision making for substances that are considered to be potentially nonthreshold acting in their toxicity (e.g., carcinogenic) requires many policy choices beyond the scientific data and is subject to considerable controversy.     

Arsenic,drinking water,and health: a position paper of the American Council on Science and Health

The purpose of this American Council on Science and Health report is to review issues and sources of uncertainty affecting assessment of potential health risks related to drinking water in the United States. Some background is included on how these issues arose, as is a review of the 1999 National Research Council report (with references to an updated version), to formulate a position based on the current science concerning how much of a risk of adverse health effects actually exists from arsenic in drinking water in the United States. ACSH concludes that there is clear evidence that chronic exposure to inorganic arsenic at concentrations of at least several hundred micrograms per liter may cause: (1) cancer of skin, bladder, lung (and possibly several other internal organs, including kidney, liver, and prostate), and (2) noncancer effects, including classic cutaneous manifestations that are distinctive and characteristic of chronic arsenic poisoning (diffuse or spotted hyperpigmentation and palmar-plantar hyperkeratoses). Noncancer effects may be multisystemic, with some evidence of peripheral vascular, cardiovascular, and cerebrovascular disease, diabetes, and adverse reproductive outcomes. Further study is needed to know if beneficial effects of arsenic in animal studies apply to humans. ACSH concludes that there is little, if any, evidence of a detrimental health effect in humans from inorganic arsenic in drinking water at the current maximum contaminant level (MCL) of 50 microg/L or below, either in the United States or elsewhere. As noted in the 1999 NRC report, "No human studies of sufficient statistical power or scope have examined whether consumption of arsenic in drinking water at the current MCL results in an increased incidence of cancer or noncancer effects" (NRC, 1999, p. 7). Based on our review, described in this article, ACSH finds that the limitations of the epidemiological data available and the state-of-the-science on the mode-of-action of arsenic toxicity, including can cer, are inadequate to support the conclusion that there are adverse health effects in the United States from arsenic in drinking water at or below the limit of 50 microg/L.     

Risk assessment of khat use in the Netherlands: A review based on adverse health effects,prevalence, criminal involvement and public order

In preparing a decision about the legal status of khat in the Netherlands, the Dutch Minister of Health requested CAM (Coordination point Assessment and Monitoring new drugs) to assess the overall risk of khat in the Netherlands. The present paper is a redraft of a report which formed the scientific basis of the risk evaluation procedure (October 2007). This report reviews the scientific data about khat available in the international literature. In addition, the report contains some information specific for the Netherlands (prevalence, availability of khat and public order aspects). The main psychoactive compounds in khat leaves are cathine and cathinone, which are some 2- to 10-fold less active than amphetamine. Acute health problems are rarely seen, and are usually related with malnutrition, social and financial problems. Khat has a low addictive potential. Chronic toxicity of khat is modest when used in low amounts, whereas at high levels, khat use is associated with adverse effects, like hypertension, heart rhythm disorders, insomnia and loss of appetite. In addition, khat users show a higher prevalence of cancers in the digestive tract. At population level, khat does not lead to specific health risks in the Netherlands, as its use is confined to East-African immigrants. A relationship between khat use and psychiatric disorders has been suggested, but the reports are contradictory, and such studies are presumably heavily confounded by posttraumatic and social stress. In the Netherlands (and other countries), khat use occasionally leads to minor disturbance of civil order in the public domain (loud talking, spitting), but is not related to criminal activities. Following the assessment, CAM estimated the overall risk potential of khat use in the Netherlands as very low. A similar conclusion may be drawn for countries with a comparable prevalence of khat use and khat related public order disturbance.     

Risk assessment of khat use in the Netherlands: a review based on adverse health effects, prevalence, criminal involvement and public order

In preparing a decision about the legal status of khat in the Netherlands, the Dutch Minister of Health requested CAM (Coordination point Assessment and Monitoring new drugs) to assess the overall risk of khat in the Netherlands. The present paper is a redraft of a report which formed the scientific basis of the risk evaluation procedure (October 2007). This report reviews the scientific data about khat available in the international literature. In addition, the report contains some information specific for the Netherlands (prevalence, availability of khat and public order aspects). The main psychoactive compounds in khat leaves are cathine and cathinone, which are some 2- to 10-fold less active than amphetamine. Acute health problems are rarely seen, and are usually related with malnutrition, social and financial problems. Khat has a low addictive potential. Chronic toxicity of khat is modest when used in low amounts, whereas at high levels, khat use is associated with adverse effects, like hypertension, heart rhythm disorders, insomnia and loss of appetite. In addition, khat users show a higher prevalence of cancers in the digestive tract. At population level, khat does not lead to specific health risks in the Netherlands, as its use is confined to East-African immigrants. A relationship between khat use and psychiatric disorders has been suggested, but the reports are contradictory, and such studies are presumably heavily confounded by posttraumatic and social stress. In the Netherlands (and other countries), khat use occasionally leads to minor disturbance of civil order in the public domain (loud talking, spitting), but is not related to criminal activities. Following the assessment, CAM estimated the overall risk potential of khat use in the Netherlands as very low. A similar conclusion may be drawn for countries with a comparable prevalence of khat use and khat related public order disturbance.     

Behavioral toxicology in the 21st century: Challenges and opportunities for behavioral scientists: Summary of a symposium presented at the annual meeting of the Neurobehavioral Teratology Society,June, 2009

The National Research Council (NRC) of the National Academies of Science recently published a report of its vision of toxicity testing in the 21st century. The report proposes that the current toxicity testing paradigm that depends upon whole-animal tests be replaced with a strategy based upon in vitro tests, in silico models and evaluations of toxicity at the human population level. These goals are intended to set in motion changes that will transform risk assessment into a process in which adverse effects on public health are predicted by quantitative structure–activity relationship (QSAR) models and data from suites of high-throughput in vitro tests. The potential roles for whole-animal testing in this futuristic vision are both various and undefined. A symposium was convened at the annual meeting of the Neurobehavioral Teratology Society in Rio Grande, Puerto Rico in June, 2009 to discuss the potential challenges and opportunities for behavioral scientists in developing and/or altering this strategy toward the ultimate goal of protecting public health from hazardous chemicals. R. Kavlock described the NRC vision, introduced the concept of the ‘toxicity pathway’ (a central guiding principle of the NRC vision), and described the current status of an initial implementation this approach with the EPA's ToxCast® program. K. Crofton described a pathway based upon disruption of thyroid hormone metabolism during development, including agents, targets, and outcomes linked by this mode of action. P. Bushnell proposed a pathway linking the neural targets and cellular to behavioral effects of acute exposure to organic solvents, whose predictive power is limited by our incomplete understanding of the complex CNS circuitry that mediates the behavioral responses to solvents. B. Weiss cautioned the audience regarding a pathway approach to toxicity testing, using the example of the developmental toxicity of phthalates, whose effects on mammalian sexual differentiation would be difficult to identify based on screening tests in vitro. Finally, D. Rice raised concerns regarding the use of data derived from toxicity screening tests to human health risk assessments. Discussion centered around opportunities and challenges for behavioral toxicologists regarding this impending paradigm shift. Opportunities include: identifying and characterizing toxicity pathways; informing the conditions and limits of extrapolation; addressing issues of susceptibility and variability; providing reality-checks on selected positives and negatives from screens; and performing targeted testing and dose-response assessments of chemicals flagged during screening. Challenges include: predicting behavior using models of complex neurobiological pathways; standardizing study designs and dependent variables to facilitate creation of databases; and managing the cost and efficiency of behavioral assessments. Thus, while progress is being made in approaching the vision of 21st century toxicology, we remain a long way from replacing whole-animal tests; indeed, some animal testing will be essential for the foreseeable future at least. Initial advances will likely provide better prioritization tools so that animal resources are used more efficiently and effectively.     

Primer for Evaluating Ecological risk at Petroleum Release Sites

ABSTRACT

Increasingly, risk-based approaches are being used to guide decision making at sites such as service stations and petroleum product terminals, where petroleum products have been inadvertently released to the soil. For example, the API Decision Support System software, DSS, evaluates site human health risk along six different routes of exposure. The American Society for Testing and Materials' Risk-Based Corrective Action (RBCA) standard, ASTM 1739, establishes a tiered framework for evaluating petroleum release sites on the basis of human health risk. Though much of the risk assessment focus has been on human health risk, regulatory agencies recognize that protection of human health may not fully protect the environment; and EPA has developed guidance on identifying ecological resources to be protected through risk-based decision making.

Not every service station or petroleum product terminal site warrants a detailed ecological risk assessment. In some cases, a simple preliminary assessment will provide sufficient information for decision making. Accordingly, the American Petroleum Institute (API) is developing a primer for site managers, to assist them in conducting this preliminary assessment, and in deciding whether more detailed ecological risk assessments are warranted. The primer assists the site manager in identifying relevant ecological receptors and habitats, in identifying chemicals and exposure pathways of concern, in developing a conceptual model of the site to guide subsequent actions, and in identifying conditions that may warrant immediate response.     

Workshop on risk assessment in reproductive and developmental toxicology: addressing the assumptions and identifying the research needs

The risk assessment process is an imprecise procedure aimed at determining a toxicant exposure level with an acceptable risk to the human population. The lack of precision is due to the uncertainties in the assumptions that must be made due to the lack of specific scientific information or knowledge of how to use certain types of data. Unfortunately, every necessary piece of information cannot be obtained for every chemical requiring a risk assessment. In order to better identify and understand some of the assumptions that are made in the risk assessment of reproductive and developmental toxicants, a workshop was organized to specifically define the assumptions underlying the risk assessments for seven specific toxicants (dibromochloropropane, dioxin, glycol ethers, heptachlor, lead, tetrahydrocannabinol, and vitamin A) and to determine the potential research which would reduce the uncertainty associated with making those assumptions. The major assumptions discussed centered around the topics of heterogeneous populations, thresholds, safety factors, exposure assessment, quantitative structure-activity relationships, and mechanisms. This report is the summary of the workshop discussions.     

Biologically Based, Quantitative Risk Assessment of Neurotoxicants

The need for biologically based, quantitative risk assessmentprocedures for noncancer endpoints such as neurotoxicity hasbeen discussed in reports by the United States Congress (Officeof Technology Assessment, OTA), National Research Council (NRC),and a federal coordinating council. According to OTA, currentattention and resources allocated to health risk assessmentresearch are inadequate and not commensurate with its impacton public health and the economy. Methods to include continuousrather than dichotomous data for neurotoxicity endpoints, biomarkersof exposure and effects, and pharmacokinetic and mechanisticdata have been proposed for neurotoxicity risk assessment butrequire further review and validation before acceptance. Thepurpose of this symposium was to examine procedures to enhancethe risk assessment process for neurotoxicants and to discusstechniques to make the process more quantitative. Accordingly,a review of the currently used safety factor risk assessmentapproach for neurotoxicants is provided along with specificexamples of how this process may be enhanced with the use ofthe benchmark dose approach. The importance of including physiologicallybased pharmacokinetic data in the risk assessment process andspecific examples of this approach is presented for neurotoxicants.The role of biomarkers of exposure and effect and mechanisticinformation in the risk assessment process are also addressed.Finally, quantitative approaches with the use of continuousneurotoxicity data are demonstrated and the outcomes comparedto those generated by currently used risk assessment procedures.     

Multiple receptors shape the estrogen response pathway and are critical considerations for the future of in vitro-based risk assessment efforts

Current in life toxicity testing paradigms are being challenged as the future of risk assessment moves towards more comprehensive mode of action/adverse outcome pathway based approaches. In particular, endocrine disruption screening is now a global activity and key initiatives in the United States focus on the use of high throughput in vitro assays to prioritize compounds for further testing of estrogen, androgen or thyroid disruption. Of these pathways, much of the emphasis to date has been on high-throughput methods for estrogenic activity primarily using ligand binding and trans-activation assays. However, as the knowledge regarding estrogen receptor signaling pathways continues to evolve, it is clear that the assumption of a simple one-receptor pathway underlying current in vitro screening assays is out of date. To develop more accurate models for estrogen-initiated pathways useful for quantitative safety assessments, we must design assays that account for the key signaling processes driving cellular dose response based on up-to-date understanding of the biological network. In this review, we summarize the state of the science for the estrogen receptor signaling network, particularly with regard to proliferative effects, and highlight gaps in current high throughput approaches. From the sum of this literature, we propose a model for the estrogen-signaling pathway that should serve as a starting point for development of new in vitro methods fit for the purpose of predicting dose response for estrogenic chemicals in the human.     

Systematic comparison of study quality criteria

Approaches for the systematic review and evaluation of chemical toxicity are currently being reconsidered, with a specific focus on the evaluation of individual studies and their integration into the overall body of evidence. This renewed interest has arisen, in part, as a result of several prominent reviews of these approaches by special committees of the National Research Council (NRC), among others. We conducted a critical evaluation of several available frameworks for evaluating study quality. We assessed the criteria separately for human, animal, and in vitro studies as well as for systematic reviews. We then evaluated commonalities across disciplines. We also considered the potential implications of applying criteria frameworks and how they bear on fundamental risk assessment questions. We found that the available frameworks within each discipline differed in terms of their intended purpose and level of guidance for decision making. All the frameworks across disciplines shared common themes, however, including the adequate reporting of specific details of study conditions and design/protocol, selection and randomization of study groups (where applicable), outcome assessment methods and applicability (e.g., validity and reliability), avoidance of selective reporting, and the consideration of potential confounders or bias. We identified the most informative study quality considerations, which will enable researchers to implement more objective and standardized methods for evaluating studies and, ultimately, improve risk assessment methods.     

Applying decision analysis in therapeutic drug monitoring: using decision trees to interpret serum theophylline concentrations

In the second of a three-part series, decision analysis is applied to therapeutic drug monitoring decisions that affect individual patients, using theophylline concentration and toxicity data to illustrate general concepts. Likelihood ratios and conditional probability curves were developed. The curves were used to determine the probability of toxicity based on the clinician's assessment of patient status and a measured serum theophylline concentration. A decision tree to "rule in" or "rule out" toxicity was constructed. Selection of a serum concentration cutoff level for classifying patients as toxic or nontoxic depends on the probabilities of the possible outcomes of the decision process and the clinician's assessment of the value of each possible outcome; therefore, no single concentration value is best for classifying patients. A decision tree was also constructed for evaluating therapeutic options when the clinician is confronted with adverse effects that may be drug related. In three prototype cases, the expected utility for discontinuing theophylline, continuing the drug at the same dosage, or lowering the dosage was determined and used to evaluate the relative worth of each therapeutic option. A more comprehensive interpretation of the serum theophylline concentration is provided by decision-analysis techniques than by observation of pharmacologic effect alone, because other factors such as merit, risk, and consequences of alternative decisions are considered.     

High-throughput in vitro profiling assays: lessons learnt from experiences at Novartis

This article reviews the use of a selection of in vitro assays implemented at Novartis and intends to address exposure and safety in early drug discovery. The authors' own experience, based on a large number of 'real' drug discovery compounds, is described to reflect on what has worked, where improvement is needed and how to best use the data for decision making. Possible strategies are discussed, and guidelines are provided on how to organise assays, extract value and contribute knowledge from the data.     

Dose response considerations in risk assessment—An overview of recent ILSI activities

This paper will provide some perspective on the role that a consideration of the dose–response has played (past), is playing (present) and will play (future) in human risk assessment with special emphasis on a number of recent activities undertaken by various components of the International Life Sciences Institute (ILSI). The dose–response is a critically important concept in every aspect of biomedical science, including toxicology. A characterization of the dose response has been recognized as one of the four essential components of risk assessment since the release of the NRC/NAS report in 1983, and understanding the dose–response curve is the basis for regulatory toxicology. The introduction of concepts such as hormesis, thresholds of toxicological concern (TTC), and dose-dependent transitions in mechanisms of toxicity have emphasized the complexities associated with a characterization of the dose–response. The transitions to emphasizing predictive toxicology, systems biology, the new ‘omics technologies, and high-throughput screening (HTS) have provided a new vision for toxicity testing. One impact of fully integrating these new concepts and technologies is that we will have unprecedented capabilities to explore the dose–response relationship, especially at low doses. How these new insights into the dose–response will affect our definition of threshold, and our understanding of the distinction between adverse and adaptive effects remain to be determined.     

Food safety: risk assessment methodology and decision-making criteria

As our scientific technology grows, risk assessment methods become more complex and, therefore, open to greater scientific debate. Risk assessment has always been a part of the regulatory notification and approval process for foods. However, the methodologies applied to risk assessment and decision-making have become diverse, dependent on a number of features, including the areas of the world in which one operates, the need to use cumulative risk assessment for pesticides and other ingredients or alternative risk assessment considerations for evaluating nontraditional or bioengineered foods. Diverse institutional structures within a single federal regulatory authority may tend to lead to diversity in risk outcomes that creates policy decisions that complicate and confuse the risk management process. On top of this challenge, decisions become more complicated by the need to examine beneficial factors of foods rather than the adverse effects of foods and food additives. Foods are a complex mixture of ingredients. Regulatory groups recognize the need to use new approaches for evaluating the safety and risks associated with foods and food additives, and to do so in a timely manner. The United States Food and Drug Administration (US FDA) in its need to ensure standards of "reasonable certainty of no harm" continues to explore alternative means to be responsive to petitioners as well as continue to examine scientifically validated means, e.g., quantitative structure-activity relationship (QSAR), and computer-assisted programs, within the approval process to assist in the evaluation of risks. Another means to improve the risk management process would include the cumulative risk assessment of pesticides that will, no doubt, be the beginning of more intensive efforts to understand cumulative exposures and the inherent risks from multiple pathways of exposure. The passage of the Food Quality Protection Act (FQPA) resulted in developing additional risk assessment methodologies and approaches to assess the potential for multiple exposures and risks. Addressing the international criteria used in decision-making related to foods safety assessment has resulted in acceptable intake values for food ingredients for carcinogens and noncarcinogens that, in general, tend to be more stringent in the United States compared to Europe. Clearly, the need for harmonization of risk assessment criteria and the impact of the decision process on regulatory approvals and safety assessment is a future need for the continued assurances of food safety. The topics presented in this paper are based on a symposium held in November 2002 at the annual meeting of the American College of Toxicology.     

Pitfalls in meta-analyses on adverse events reported from clinical trials

In recent years, comparative effectiveness research has been more aggressively pursued as a means to improve health care, including systematic reviews and meta-analyses to inform health policy decision making. Because most clinical trials have pre-specified approaches to collecting data on efficacy, the value of systematic reviews and meta-analyses in assessing efficacy outcomes is generally accepted. In contrast, collection of data on adverse events is seldom well structured. Hence, the methodological considerations for comparing adverse events from such non-aligned sources differ substantially from those for comparing efficacy endpoints. We address several important pitfalls in performing systematic reviews and meta-analyses on adverse events in clinical trials, and we offer recommendations for remedies. Some pitfalls arise from the fact that adverse events often are not the primary endpoints in clinical trials, hence incomplete reporting, inconsistent event definitions, various level of effort in reporting unexpected adverse events, and inappropriate use of statistical testing. Others are posed by certain important characteristics of adverse events data. The very concept of "adverse events" may skew the ascertainment, attribution, and reporting of the events. In addition, problems for meta-analysis methods arise in situations involving zero or rare events and withdrawal or loss to follow-up because of adverse events. We highlight recent initiatives that may improve the assessment and cross-study summary of adverse events. We anticipate that future guidance for conducting systematic reviews and meta-analyses will evolve to address the important methodological pitfalls we highlight here, and the practice of assessing the totality of evidence on drug safety will be improved.     

Adolescent Risk Taking,Cocaine Self-Administration,and Striatal Dopamine Signaling

Poor decision making and elevated risk taking, particularly during adolescence, have been strongly linked to drug use; however the causal relationships among these factors are not well understood. To address these relationships, a rat model (the Risky Decision-making Task; RDT) was used to determine whether individual differences in risk taking during adolescence predict later propensity for cocaine self-administration and/or whether cocaine self-administration causes alterations in risk taking. In addition, the RDT was used to determine how risk taking is modulated by dopamine signaling, particularly in the striatum. Results from these experiments indicated that greater risk taking during adolescence predicted greater intake of cocaine during acquisition of self-administration in adulthood, and that adult cocaine self-administration in turn caused elevated risk taking that was present following 6 weeks of abstinence. Greater adolescent risk taking was associated with lower striatal D2 receptor mRNA expression, and pharmacological activation of D2/3 receptors in the ventral, but not dorsal, striatum induced a decrease in risk taking. These findings indicate that the relationship between elevated risk taking and cocaine self-administration is bi-directional, and that low striatal D2 receptor expression may represent a predisposing factor for both maladaptive decision making and cocaine use. Furthermore, these findings suggest that striatal D2 receptors represent a therapeutic target for attenuating maladaptive decision making when choices include risk of adverse consequences.