Assessing Potential Human Health Hazards and Benefits from Subtherapeutic Antibiotics in the United States: Tetracyclines as a Case Study

Many scientists, activists, regulators, and politicians have expressed urgent concern that using antibiotics in food animals selects for resistant strains of bacteria that harm human health and bring nearer a “postantibiotic era” of multidrug resistant “super‐bugs.” Proposed political solutions, such as the Preservation of Antibiotics for Medical Treatment Act (PAMTA), would ban entire classes of subtherapeutic antibiotics (STAs) now used for disease prevention and growth promotion in food animals. The proposed bans are not driven by formal quantitative risk assessment (QRA), but by a perceived need for immediate action to prevent potential catastrophe. Similar fears led to STA phase‐outs in Europe a decade ago. However, QRA and empirical data indicate that continued use of STAs in the United States has not harmed human health, and bans in Europe have not helped human health. The fears motivating PAMTA contrast with QRA estimates of vanishingly small risks. As a case study, examining specific tetracycline uses and resistance patterns suggests that there is no significant human health hazard from continued use of tetracycline in food animals. Simple hypothetical calculations suggest an unobservably small risk (between 0 and 1.75E‐11 excess lifetime risk of a tetracycline‐resistant infection), based on the long history of tetracycline use in the United States without resistance‐related treatment failures. QRAs for other STA uses in food animals also find that human health risks are vanishingly small. Whether such QRA calculations will guide risk management policy for animal antibiotics in the United States remains to be seen.     

Animal Antibiotic Use and Human Health: No Expert Judgment is Needed to Determine that Reducing Cases Reduces Risk

In his comments on our Rapid Risk Rating Technique (RRRT), Dr. Claycamp states that "Cox and Popken were silent on the pivotal expert judgment subsumed in their method: quality weights for illnesses caused by antimicrobial-resistant and antimicrobial-sensitive microbes are tacitly assumed to be equal." However, contrary to this comment, we explicitly provide separate quality weights for antimicrobial-resistant and antimicrobial-sensitive illnesses (with different values, based on QALYs lost per illness, illustrated in our article). Thus, our model already addresses Dr. Claycamp's central concern. Moreover, since withdrawing macrolides and fluoroquinolones from use as animal antibiotics is projected to cause more of both types of illnesses—antimicrobial-resistant and antimicrobial-sensitive—than continuing to use them would, our conclusion that such withdrawals would be poor public health policy is completely robust to changes in the quality weights. Our human health impacts assessment is therefore indeed immune from the "expert judgments in risk management" discussed by Dr. Claycamp .     

Reproductive and Developmental Risks from Ethylene Oxide: A Probabilistic Characterization of Possible Regulatory Thresholds

Ethylene oxide is a gas produced in large quantities in the United States that is used primarily as a chemical intermediate in the production of ethylene glycol, propylene glycol, non-ionic surfactants, ethanolamines, glycol ethers, and other chemicals. It has been well established that ethylene oxide can induce cancer, genetic, reproductive and developmental, and acute health effects in animals. The U.S. Environmental Protection Agency is currently developing both a cancer potency factor and a reference concentration (RfC) for ethylene oxide. This study used the rich database on the reproductive and developmental effects of ethylene oxide to develop a probabilistic characterization of possible regulatory thresholds for ethylene oxide. This analysis was based on the standard regulatory approach for noncancer risk assessment, but involved several innovative elements, such as: (1) the use of advanced statistical methods to account for correlations in developmental outcomes among littermates and allow for simultaneous control of covariates (such as litter size); (2) the application of a probabilistic approach for characterizing the uncertainty in extrapolating the animal results to humans; and (3) the use of a quantitative approach to account for the variation in heterogeneity among the human population. This article presents several classes of results, including: (1) probabilistic characterizations of ED10s for two quantal reproductive outcomes-resorption and fetal death, (2) probabilistic characterizations of one developmental outcome-the dose expected to yield a 5% reduction in fetal (or pup) weight, (3) estimates of the RfCs that would result from using these values in the standard regulatory approach for noncancer risk assessment, and (4) a probabilistic characterization of the level of ethylene oxide exposure that would be expected to yield a 1/1,000 increase in the risk of reproductive or developmental outcomes in exposed human populations.     

Rapid Benefit-Risk Assessments: No Escape from Expert Judgments in Risk Management

The "human health impacts assessment" described by Cox and Popken (this issue) is intended to be a benefit-risk tool that avoids pitfalls of using expert judgments for policy analysis or during strict application of the precautionary principle in risk management. The proposed benefit-risk calculation uses numerous assumptions and suppositions to calculate a ratio of quality-adjusted life years (QALYs) lost for the number of human illness days prevented by the use of a food-animal antimicrobial drug, to the number of human illness days caused by the use of the antimicrobial drug. Assumptions about data--e.g., expert judgments on the representativeness of parameter estimates--are commonly used in risk assessment and risk management, including Cox and Popken's method. Cox and Popken apply the technique to specific examples of enrofloxacin and macrolides antimicrobial drugs, sometimes used in broiler chickens for human food. Although enthusiastically portrayed as a straightforward calculation of QALYs lost for two decision alternatives, Cox and Popken were silent on the pivotal expert judgment subsumed in their method: quality weights for illnesses caused by antimicrobial-resistant and antimicrobial-sensitive microbes are tacitly assumed to be equal. Yet, the costs in terms of prolonged illness, additional medications, repeat medical visits, and dread of more serious sequelae are expected to differ substantially for antimicrobial-resistant versus antimicrobial-sensitive illnesses. Despite their enthusiasm to the contrary, the "human health impacts assessment" by Cox and Popken is not immune from expert judgments in risk management.     

Quantitative risk assessment-epidemic curve prediction model for leafy green outbreak investigation

The objective of this study was to leverage quantitative risk assessment to investigate possible root cause(s) of foodborne illness outbreaks related to Shiga toxin-producing Escherichia coli O157:H7 (STEC O157) infections in leafy greens in the United States. To this end, we developed the FDA leafy green quantitative risk assessment epidemic curve prediction model (FDA-LG QRA-EC) that simulated the lettuce supply chain. The model was used to predict the number of reported illnesses and the epidemic curve associated with lettuce contaminated with STEC O157 for a wide range of scenarios representing various contamination conditions and facility processing/sanitation practices. Model predictions were generated for fresh-cut and whole lettuce, quantifying the differing impacts of facility processing and home preparation on predicted illnesses. Our model revealed that the timespan (i.e., number of days with at least one reported illness) and the peak (i.e., day with the most predicted number of reported illnesses) of the epidemic curve of a STEC O157-lettuce outbreak were not strongly influenced by facility processing/sanitation practices and were indications of contamination pattern among incoming lettuce batches received by the facility or distribution center. Through comparisons with observed number of illnesses from recent STEC O157-lettuce outbreaks, the model identified contamination conditions on incoming lettuce heads that could result in an outbreak of similar size, which can be used to narrow down potential root cause hypotheses.     

The Use of Risk Assessment to Decide the Control Strategy for Bluetongue in Italian Ruminant Populations

The affiliation, assessment and management of risks is a traditional part of veterinary medicine. In the past, veterinary services involved in this type of activity usually assessed risks qualitatively. However, since the 1990s, quantitative methods have become increasingly important. The establishment of the World Trade Organization in 1994, and the promulgation of its Agreement on the Application of Sanitary and Phytosanitary Measures (the "SPS Agreement") led to an increased application of import risk analysis and to significant improvements in the methodology of risk analysis as applied to international trade policy for animals and animal products. However, there was very little development of risk analysis in veterinary fields other than international trade and management of health risks to consumers of animal products and little has been published on its use in the choice and definition of control or prophylaxis strategies for animal diseases. This article describes a quantitative risk assessment, which was undertaken in Italy to help choose an appropriate national response strategy following an incursion of bluetongue, an infectious disease of sheep and goats. The results obtained in this study support the use of risk analysis as a tool to assist in choosing an appropriate animal disease management strategy. The use of risk analysis in the evaluation of disease management strategies also offers advantages in international trade. It makes easier the comparison of different strategies applied in the various countries, and thus facilitates the assessment of equivalence of the guarantees provided by different strategies.     

Human Health Risk Assessment of Penicillin/Aminopenicillin Resistance in Enterococci Due to Penicillin Use in Food Animals

Penicillin and ampicillin drugs are approved for use in food animals in the United States to treat, control, and prevent diseases, and penicillin is approved for use to improve growth rates in pigs and poultry. This article considers the possibility that such uses might increase the incidence of ampicillin-resistant Enterococcus faecium (AREF) of animal origin in human infections, leading to increased hospitalization and mortality due to reduced response to ampicillin or penicillin. We assess the risks from continued use of penicillin-based drugs in food animals in the United States, using several assumptions to overcome current scientific uncertainties and data gaps. Multiplying the total at-risk population of intensive care unit (ICU) patients by a series of estimated factors suggests that not more than 0.04 excess mortalities per year (under conservative assumptions) to 0.14 excess mortalities per year (under very conservative assumptions) might be prevented in the whole U.S. population if current use of penicillin drugs in food animals were discontinued and if this successfully reduced the prevalence of AREF infections among ICU patients. These calculations suggest that current penicillin usage in food animals in the United States presents very low (possibly zero) human health risks.     

Climate Change and Human Health: Estimating Avoidable Deaths and Disease

Human population health has always been central in the justification for sustainable development but nearly invisible in the United Nations Framework Convention on Climate Change negotiations. Current scientific evidence indicates that climate change will contribute to the global burden of disease through increases in diarrhoeal disease, vector-borne disease, and malnutrition, and the health impacts of extreme weather and climate events. A few studies have estimated future potential health impacts of climate change but often generate little policy-relevant information. Robust estimates of future health impacts rely on robust projections of future disease patterns. The application of a standardized and established methodology has been developed to quantify the impact of climate change in relation to different greenhouse gas emission scenarios. All health risk assessments are necessarily biased toward conservative best-estimates of health effects that are easily measured. Global, regional, and national risk assessments can take no account of irreversibility, or plausible low-probability events with potentially very high burdens on human health. There is no "safe limit" of climate change with respect to health impacts as health systems in some regions do not adequately cope with the current climate variability. Current scientific methods cannot identify global threshold health effects in order for policymakers to regulate a "tolerable" amount of climate change. We argue for the need for more research to reduce the potential impacts of climate change on human health, including the development of improved methods for quantitative risk assessment. The large uncertainty about the future effects of climate change on human population health should be a reason to reduce greenhouse gas emissions, and not a reason for inaction.     

Selecting human health metrics for environmental decision-support tools.

Environmental decision‐support tools often predict a multitude of different human health effects due to environmental stressors. The accounting and aggregating of these morbidity and mortality outcomes is key to support decision making and can be accomplished by different methods that we call human health metrics. This article attempts to answer two questions: Does it matter which metric is chosen? and What are the relevant characteristics of these metrics in environmental applications? Three metrics (quality adjusted life years (QALYs), disability adjusted life years (DALYs), and willingness to pay (WTP)) have been applied to the same diverse set of health effects due to environmental impacts. In this example, the choice of metric mattered for the ranking of these environmental impacts and it was found for this example that WTP was dominated by mortality outcomes. Further, QALYs and DALYs are sensitive to mild illnesses that affect large numbers of people and the severity of these mild illnesses are difficult to assess. Eight guiding questions are provided in order to help select human health metrics for environmental decision‐support tools. Since health metrics tend to follow the paradigm of utility maximization, these metrics may be supplemented with a semi‐quantitative discussion of distributional and ethical aspects. Finally, the magnitude of age‐dependent disutility due to mortality for both monetary and nonmonetary metrics may bear the largest practical relevance for future research.     

An overview of the Salmonella enteritidis risk assessment for shell eggs and egg products.

This article summarizes a quantitative microbial risk assessment designed to characterize the public health impact of consumption of shell eggs and egg products contaminated with Salmonella Enteritidis (SE). This risk assessment's objectives were to: (1) establish the baseline risk of foodborne illness from SE, (2) identify and evaluate potential risk mitigation strategies, and (3) identify data gaps related to future research efforts. The risk assessment model has five modules. The Egg Production module estimates the number of eggs produced that are SE-contaminated. Shell Egg Processing, Egg Products Processing, and Preparation & Consumption modules estimate the increase or decrease in the numbers of SE organisms in eggs or egg products as they pass through storage, transportation, processing, and preparation. A Public Health Outcomes module then calculates the incidence of illnesses and four clinical outcomes, as well as the cases of reactive arthritis associated with SE infection following consumption. The baseline model estimates an average production of 2.3 million SE-contaminated shell eggs/year of the estimated 69 billion produced annually and predicts an average of 661,633, human illnesses per year from consumption of these eggs. The model estimates approximately 94% of these cases recover without medical care, 5% visit a physician, an additional 0.5% are hospitalized, and 0.05% result in death. The contribution of SE from commercially pasteurized egg products was estimated to be negligible. Five mitigation scenarios were selected for comparison of their individual and combined effects on the number of human illnesses. Results suggest that mitigation in only one segment of the farm-to-table continuum will be less effective than several applied in different segments. Key data gaps and areas for future research include the epidemiology of SE on farms, the bacteriology of SE in eggs, human behavior in food handling and preparation, and human responses to SE exposure.     

New Data,Strategies, and Insights for Listeria monocytogenes Dose‐Response Models: Summary of an Interagency Workshop, 2011

Listeria monocytogenes is a leading cause of hospitalization, fetal loss, and death due to foodborne illnesses in the United States. A quantitative assessment of the relative risk of listeriosis associated with the consumption of 23 selected categories of ready‐to‐eat foods, published by the U.S. Department of Health and Human Services and the U.S. Department of Agriculture in 2003, has been instrumental in identifying the food products and practices that pose the greatest listeriosis risk and has guided the evaluation of potential intervention strategies. Dose‐response models, which quantify the relationship between an exposure dose and the probability of adverse health outcomes, were essential components of the risk assessment. However, because of data gaps and limitations in the available data and modeling approaches, considerable uncertainty existed. Since publication of the risk assessment, new data have become available for modeling L. monocytogenes dose‐response. At the same time, recent advances in the understanding of L. monocytogenes pathophysiology and strain diversity have warranted a critical reevaluation of the published dose‐response models. To discuss strategies for modeling L. monocytogenes dose‐response, the Interagency Risk Assessment Consortium (IRAC) and the Joint Institute for Food Safety and Applied Nutrition (JIFSAN) held a scientific workshop in 2011 (details available at http://foodrisk.org/irac/events/ ). The main findings of the workshop and the most current and relevant data identified during the workshop are summarized and presented in the context of L. monocytogenes dose‐response. This article also discusses new insights on dose‐response modeling for L. monocytogenes and research opportunities to meet future needs.     

The Contrast Between Risk Assessment and Rules of Evidence in the Context of International Trade Disputes: Can the U.S. Experience Inform the Process?

Risk assessment provides a formalized process to evaluate human, animal, and ecological responses associated with exposure to environmental agents. The purpose of risk assessment is to answer two related questions.

• ? How likely is an (adverse) event to occur?
• ? If it does, how severe will the impact be?

In the United States, the science of risk assessment has evolved out of the necessity to make public health decisions in the face of scientific uncertainty. Its basic propositions have been established over the past three decades and its applications have impacted virtually every aspect of public health and environmental protection in many countries, including the United States. More recently, the World Trade Organization's (WTO) dispute‐settlement process has provided additional incentive for the reliance on risk assessments internationally through the requirement that member countries be able to provide scientific justification, based on a risk assessment, for public health and environmental regulatory measures that are challenged. The purpose of this article is to review the history of risk assessment in the United States, emphasizing the development of both its scientific and policy aspects, as one example of the development of institutional capacity for risk assessment. This article discusses the importance of the social, political, and economic contexts of risk assessment and risk management in shaping the approaches taken while highlighting the reality that the analytic or risk assessment part of the decision‐making process, in the absence of scientific data, can be completed only by inserting inferences, or policy judgments, which may differ among countries. This article recognizes these differences, and the consequent difference between risk assessment that incorporates public health protective assumptions and the rules of evidence that seek to answer questions of causality, and discusses implications for the WTO dispute‐settlement process. It further explores the value of country‐specific risk assessment guidelines to facilitate consistency within a country along with the appropriateness and feasibility of international risk assessment guidelines.     

Quantifying Human Health Risks from Virginiamycin Used in Chickens

The streptogramin antimicrobial combination Quinupristin-Dalfopristin (QD) has been used in the United States since late 1999 to treat patients with vancomycin-resistant Enterococcus faecium (VREF) infections. Another streptogramin, virginiamycin (VM), is used as a growth promoter and therapeutic agent in farm animals in the United States and other countries. Many chickens test positive for QD-resistant E. faecium, raising concern that VM use in chickens might compromise QD effectiveness against VREF infections by promoting development of QD-resistant strains that can be transferred to human patients. Despite the potential importance of this threat to human health, quantifying the risk via traditional farm-to-fork modeling has proved extremely difficult. Enough key data (mainly on microbial loads at each stage) are lacking so that such modeling amounts to little more than choosing a set of assumptions to determine the answer. Yet, regulators cannot keep waiting for more data. Patients prescribed QD are typically severely ill, immunocompromised people for whom other treatment options have not readily been available. Thus, there is a pressing need for sound risk assessment methods to inform risk management decisions for VM/QD using currently available data. This article takes a new approach to the QD-VM risk modeling challenge. Recognizing that the usual farm-to-fork ("forward chaining") approach commonly used in antimicrobial risk assessment for food animals is unlikely to produce reliable results soon enough to be useful, we instead draw on ideas from traditional fault tree analysis ("backward chaining") to reverse the farm-to-fork process and start with readily available human data on VREF case loads and QD resistance rates. Combining these data with recent genogroup frequency data for humans, chickens, and other sources (Willems et al., 2000, 2001) allows us to quantify potential human health risks from VM in chickens in both the United States and Australia, two countries where regulatory action for VM is being considered. We present a risk simulation model, thoroughly grounded in data, that incorporates recent nosocomial transmission and genetic typing data. The model is used to estimate human QD treatment failures over the next five years with and without continued VM use in chickens. The quantitative estimates and probability distributions were implemented in a Monte Carlo simulation model for a five-year horizon beginning in the first quarter of 2002. In Australia, a Q1-2002 ban of virginiamycin would likely reduce average attributable treatment failures by 0.35 x 10(-3) cases, expected mortalities by 5.8 x 10(-5) deaths, and life years lost by 1.3 x 10(-3) for the entire population over five years. In the United States, where the number of cases of VRE is much higher, a 1Q-2002 ban on VM is predicted to reduce average attributable treatment failures by 1.8 cases in the entire population over five years; expected mortalities by 0.29 cases; and life years lost by 6.3 over a five-year period. The model shows that the theoretical statistical human health benefits of a VM ban range from zero to less than one statistical life saved in both Australia and the United States over the next five years and are rapidly decreasing. Sensitivity analyses indicate that this conclusion is robust to key data gaps and uncertainties, e.g., about the extent of resistance transfer from chickens to people.     

Uncertainties in the Link Between Global Climate Change and Predicted Health Risks from Pollution: Hexachlorobenzene (HCB) Case Study Using a Fugacity Model

Industrial societies have altered the earth's environment in ways that could have important, long-term ecological, economic, and health implications. In this paper, we examine the extent to which uncertainty about global climate change could impact the precision of predictions of secondary outcomes such as health impacts of pollution. Using a model that links global climate change with predictions of chemical exposure and human health risk in the Western region of the United States of America (U.S.), we define parameter variabilities and uncertainties and we characterize the resulting outcome variance. As a case study, we consider the public health consequences from releases of hexachlorobenzene (HCB), a ubiquitous multimedia pollutant. By constructing a matrix that links global environmental change both directly and indirectly to potential human-health effects attributable to HCB released into air, soil, and water, we define critical parameter variances in the health risk estimation process. We employ a combined uncertainty/sensitivity analysis to investigate how HCB releases are affected by increasing atmospheric temperature and the accompanying climate alterations that are anticipated. We examine how such uncertainty impacts both the expected magnitude and calculational precision of potential human exposures and health effects. This assessment reveals that uncertain temperature increases of up to 5°C have little impact on either the magnitude or precision of the public-health consequences estimated under existing climate variations for HCB released into air and water in the Western region of the U.S.     

One Agency's Use of Risk Assessment and Risk Communication1

Few organizations have the courage to evaluate their own use of risk assessment (identifying hazards and estimating their probability and magnitude) and risk communication (interacting with internal and external stakeholder groups about risks). The USDA Animal and Plant Health Inspection Service (APHIS) wants to enhance its overall risk analysis process for managing a wide range of risks to animals, plants, and human health. We gathered survey data for a baseline of APHIS professionals’ understanding and use of risk assessment and risk communication. APHIS professionals spend a surprisingly large share of their time communicating about risks. They perceive that risk estimates influence decisions, but that risk estimates should have more influence. Respondents reported little opposition to APHIS risk management decisions, and little use of channels such as USDA Extension Service for disseminating risk messages. Substantial variance across responses is explained mostly by differences in the roles of the 11 work units (now 10) within the agency. Location also contributes to the variance. Demographic variables seem less important.     

The Impact of Social Amplification and Attenuation of Risk and the Public Reaction to Mad Cow Disease in Canada

Following the detection of bovine spongiform encephalopathy (BSE) in Canada, and subsequently in the United States, confidence in the safety of beef products remained high. Consumers actually increased their consumption of beef slightly after the news of an increased risk from mad cow disease, which has been interpreted as public support for beef farmers and confidence in government regulators. The Canadian public showed a markedly different reaction to the news of domestic BSE than the furious and panicked responses observed in the United Kingdom, Germany, and Japan. Using the social amplification of risk framework, we show that, while other countries displayed social amplification of risk, Canada experienced a social attenuation of risk. The attenuated reaction in Canada toward mad cow disease and increased human health risks from variant Creutzfeldt-Jakob disease (vCJD) was due to the social context at the time when BSE was discovered domestically. Mortality, morbidity, and psychosocial impacts resulting from other major events such as severe acute respiratory syndrome (SARS), West Nile virus (WNV), and the U.S.-Iraq war made the theoretical risks of BSE and vCJD a lower priority, reducing its concern as a risk issue.     

Cooperation Versus Confrontation: A Comparison of Approaches to Environmental Risk Management in Japan and the United States1

This paper compares approaches to environmental risk management in Japan and the United States. The paper includes an historical examination of two case studies of environmental risk management: synthetic detergents and lead in gasoline. In addition, the paper discusses several important differences between Japan and the United States, including (a) different attitudes toward separating environmental risk management from environmental risk assessment, and (b) different approaches toward environmental risk management. Specifically, the Japanese approach is based largely on a cooperative model of risk management, with a strong emphasis on negotiation and consensus-building, while the U.S. approach is based largely on a confrontational model of risk management, with a strong emphasis on rigorous scientific analysis and open adverserial processes.