Quantifying Potential Human Health Impacts of Animal Antibiotic Use: Enrofloxacin and Macrolides in Chickens

Use of similar or identical antibiotics in both human and veterinary medicine has come under increasing scrutiny by regulators concerned that bacteria resistant to animal antibiotics will infect people and resist treatment with similar human antibiotics, leading to excess illnesses and deaths. Scientists, regulators, and interest groups in the United States and Europe have urged bans on nontherapeutic and some therapeutic uses of animal antibiotics to protect human health. Many regulators and public health experts have also expressed dissatisfaction with the perceived limitations of quantitative risk assessment and have proposed alternative qualitative and judgmental approaches ranging from "attributable fraction" estimates to risk management recommendations based on the precautionary principle or on expert judgments about the importance of classes of compounds in human medicine. This article presents a more traditional quantitative risk assessment of the likely human health impacts of continuing versus withdrawing use of fluoroquinolones and macrolides in production of broiler chickens in the United States. An analytic framework is developed and applied to available data. It indicates that withdrawing animal antibiotics can cause far more human illness-days than it would prevent: the estimated human BENEFIT:RISK health ratio for human health impacts of continued animal antibiotic use exceeds 1,000:1 in many cases. This conclusion is driven by a hypothesized causal sequence in which withdrawing animal antibiotic use increases illnesses rates in animals, microbial loads in servings from the affected animals, and hence human health risks. This potentially important aspect of human health risk assessment for animal antibiotics has not previously been quantified.     

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.     

Communicating Food Risks in an Era of Growing Public Distrust: Three Case Studies

The communication and regulation of risk has changed significantly over the past 30 years in Europe and to a noticeable but lesser extent in the United States. In Europe, this is partly due to a series of regulatory mishaps, ranging from mad cow disease in the United Kingdom to contamination of the blood supply in France. In the United States, general public confidence in the American government has been gradually declining for more than three decades, driven by a mix of cultural and political conflicts like negative political advertising, a corrosive news media, and cuts in regulatory budgets. While the former approach is based on an objective assessment of the risk, the latter is driven more by the perception of the risk, consumer sentiment, political will, and sectoral advocacy. In this article, the author examines three U.S.‐based food case studies (acrylamide, bisphenol A, and artificial food colorings) where regulations at the local and state levels are increasingly being based on perceived risk advocacy rather than on the most effective response to the risk, be it to food safety or public health, as defined by regulatory interpretation of existing data. In the final section, the author puts forward a series of recommendations for how U.S.‐based regulators can best handle those situations where the perceived risk is markedly different from the fact‐based risk, such as strengthening the communication departments of food regulatory agencies, training officials in risk communication, and working more proactively with neutral third‐party experts.     

Hypothetical Fears and Quantitative Risk Analysis

Hypothetical fears are concepts, not quantities. Their conceptual nature makes impractical conventional quantitative risk analyses (QRA) based on benefit/cost/risk, so they become an unmeasured influence in national decision making. The decision process involves two steps, the Analytic Stage (QRA based) and the Priority Stage (resource allocation competition). This article suggests that a quantitative estimate of the social cost of fear reduction to acceptable levels be used as a surrogate QRA input to the Priority Stage.     

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.     

Precautionary Regulation in Europe and the United States: A Quantitative Comparison

Much attention has been addressed to the question of whether Europe or the United States adopts a more precautionary stance to the regulation of potential environmental, health, and safety risks. Some commentators suggest that Europe is more risk-averse and precautionary, whereas the United States is seen as more risk-taking and optimistic about the prospects for new technology. Others suggest that the United States is more precautionary because its regulatory process is more legalistic and adversarial, while Europe is more lax and corporatist in its regulations. The flip-flop hypothesis claims that the United States was more precautionary than Europe in the 1970s and early 1980s, and that Europe has become more precautionary since then. We examine the levels and trends in regulation of environmental, health, and safety risks since 1970. Unlike previous research, which has studied only a small set of prominent cases selected nonrandomly, we develop a comprehensive list of almost 3,000 risks and code the relative stringency of regulation in Europe and the United States for each of 100 risks randomly selected from that list for each year from 1970 through 2004. Our results suggest that: (a) averaging over risks, there is no significant difference in relative precaution over the period, (b) weakly consistent with the flip-flop hypothesis, there is some evidence of a modest shift toward greater relative precaution of European regulation since about 1990, although (c) there is a diversity of trends across risks, of which the most common is no change in relative precaution (including cases where Europe and the United States are equally precautionary and where Europe or the United States has been consistently more precautionary). The overall finding is of a mixed and diverse pattern of relative transatlantic precaution over the period.     

Does Concern‐Driven Risk Management Provide a Viable Alternative to QRA?

This article discusses a concept of concern-driven risk management, in which qualitative expert judgments about whether concerns warrant specified risk management interventions are used in preference to quantitative risk assessment (QRA) to guide risk management decisions. Where QRA emphasizes formal quantitative assessment of the probable consequences caused by the recommended actions, and comparison to the probable consequences of alternatives, including the status quo, concern-driven risk management instead emphasizes perceived urgency or severity of the situation motivating recommended interventions. In many instances, especially those involving applications of the precautionary principle, no formal quantification or comparison of probable consequences for alternative decisions is seen as being necessary (or, perhaps, possible or desirable) prior to implementation of risk management measures. Such concern-driven risk management has been recommended by critics of QRA in several areas of applied risk management. Based on case studies and psychological literature on the empirical performance of judgment-based approaches to decision making under risk and uncertainty, we conclude that, although concern-driven risk management has several important potential political and psychological advantages over QRA, it is not clear that it performs better than (or as well as) QRA in identifying risk management interventions that successfully protect human health or achieve other desired consequences. Therefore, those who advocate replacing QRA with concern-driven alternatives, such as expert judgment and consensus decision processes, should assess whether their recommended alternatives truly outperform QRA, by the criterion of producing preferred consequences, before rejecting the QRA paradigm for practical applications.     

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.     

Quantitative Assessment of the Health Risk for Livestock When Animal Viruses Are Applied in Human Oncolytic Therapy: A Case Study for Seneca Valley Virus

Some viruses cause tumor regression and can be used to treat cancer patients; these viruses are called oncolytic viruses. To assess whether oncolytic viruses from animal origin excreted by patients pose a health risk for livestock, a quantitative risk assessment (QRA) was performed to estimate the risk for the Dutch pig industry after environmental release of Seneca Valley virus (SVV). The QRA assumed SVV excretion in stool by one cancer patient on Day 1 in the Netherlands, discharge of SVV with treated wastewater into the river Meuse, downstream intake of river water for drinking water production, and consumption of this drinking water by pigs. Dose–response curves for SVV infection and clinical disease in pigs were constructed from experimental data. In the worst scenario (four log₁₀ virus reduction by drinking water treatment and a farm with 10,000 pigs), the infection risk is less than 1% with 95% certainty. The risk of clinical disease is almost seven orders of magnitude lower. Risks may increase proportionally with the numbers of treated patients and days of virus excretion. These data indicate that application of wild‐type oncolytic animal viruses may infect susceptible livestock. A QRA regarding the use of oncolytic animal virus is, therefore, highly recommended. For this, data on excretion by patients, and dose–response parameters for infection and clinical disease in livestock, should be studied.     

Quantitative Risk Assessment Modeling for Nonhomogeneous Urban Road Tunnels

Urban road tunnels provide an increasingly cost‐effective engineering solution, especially in compact cities like Singapore. For some urban road tunnels, tunnel characteristics such as tunnel configurations, geometries, provisions of tunnel electrical and mechanical systems, traffic volumes, etc. may vary from one section to another. These urban road tunnels that have characterized nonuniform parameters are referred to as nonhomogeneous urban road tunnels. In this study, a novel quantitative risk assessment (QRA) model is proposed for nonhomogeneous urban road tunnels because the existing QRA models for road tunnels are inapplicable to assess the risks in these road tunnels. This model uses a tunnel segmentation principle whereby a nonhomogeneous urban road tunnel is divided into various homogenous sections. Individual risk for road tunnel sections as well as the integrated risk indices for the entire road tunnel is defined. The article then proceeds to develop a new QRA model for each of the homogeneous sections. Compared to the existing QRA models for road tunnels, this section‐based model incorporates one additional top event—toxic gases due to traffic congestion—and employs the Poisson regression method to estimate the vehicle accident frequencies of tunnel sections. This article further illustrates an aggregated QRA model for nonhomogeneous urban tunnels by integrating the section‐based QRA models. Finally, a case study in Singapore is carried out.     

Influence of Safety Measures on the Risks of Transporting Dangerous Goods Through Road Tunnels

Quantitative risk assessment (QRA) models are used to estimate the risks of transporting dangerous goods and to assess the merits of introducing alternative risk reduction measures for different transportation scenarios and assumptions. A comprehensive QRA model recently was developed in Europe for application to road tunnels. This model can assess the merits of a limited number of "native safety measures." In this article, we introduce a procedure for extending its scope to include the treatment of a number of important "nonnative safety measures" of interest to tunnel operators and decisionmakers. Nonnative safety measures were not included in the original model specification. The suggested procedure makes use of expert judgment and Monte Carlo simulation methods to model uncertainty in the revised risk estimates. The results of a case study application are presented that involve the risks of transporting a given volume of flammable liquid through a 10-km road tunnel.     

Quantitative Assessment of Human MRSA Risks from Swine

The public health community, news media, and members of the general public have expressed significant concern that methicillin‐resistant Staphylococcus aureus (MRSA) transmitted from pigs to humans may harm human health. Studies of the prevalence and dynamics of swine‐associated (ST398) MRSA have sampled MRSA at discrete points in the presumed causative chain leading from swine to human patients, including sampling bacteria from live pigs, retail meats, farm workers, and hospital patients. Nonzero prevalence is generally interpreted as indicating a potential human health hazard from MRSA infections, but quantitative assessments of resulting risks are not usually provided. This article integrates available data from several sources to construct a conservative (plausible upper bound) probability estimate for the actual human health harm (MRSA infections and fatalities) arising from ST398‐MRSA from pigs. The model provides plausible upper bounds of approximately one excess human infection per year among all U.S. pig farm workers, and one human infection per 31 years among the remaining total population of the United States. These results assume the possibility of transmission events not yet observed, so additional data collection may reduce these estimates further.     

MANAGED COMPETITION IN HEALTH INSURANCE

Rising healthcare costs have sparked debate about the best way to provide high‐quality affordable health insurance. We discuss the potential for regulated insurance markets to outperform single‐payer public insurance. We use as an example the private Medicare plans that now provide insurance to almost a third of seniors in the United States. The evidence suggests that private plans can limit costs and potentially appeal to enrollees, and that well‐designed risk adjustment can mitigate market failures due to adverse selection. However, fostering competition between insurers, especially in smaller markets, is difficult. We discuss how future research might illuminate the relative advantages of public and private health insurance.     

Perceived Risks of Conventional and Organic Produce: Pesticides, Pathogens, and Natural Toxins

Public risk perceptions and demand for safer food are important factors shaping agricultural production practices in the United States. Despite documented food safety concerns, little attempt has been made to elicit consumers' subjective risk judgments for a range of food safety hazards or to identify factors most predictive of perceived food safety risks. In this study, over 700 conventional and organic fresh produce buyers in the Boston area were surveyed for their perceived food safety risks. Survey results showed that consumers perceived relatively high risks associated with the consumption and production of conventionally grown produce compared with other public health hazards. For example, conventional and organic food buyers estimated the median annual fatality rate due to pesticide residues on conventionally grown food to be about 50 per million and 200 per million, respectively, which is similar in magnitude to the annual mortality risk from motor vehicle accidents in the United States. Over 90% of survey respondents also perceived a reduction in pesticide residue risk associated with substituting organically grown produce for conventionally grown produce, and nearly 50% perceived a risk reduction due to natural toxins and microbial pathogens. Multiple regression analyses indicate that only a few factors are consistently predictive of higher risk perceptions, including feelings of distrust toward regulatory agencies and the safety of the food supply. A variety of factors were found to be significant predictors of specific categories of food hazards, suggesting that consumers may view food safety risks as dissimilar from one another. Based on study findings, it is recommended that future agricultural policies and risk communication efforts utilize a comparative risk approach that targets a range of food safety hazards.     

A Look at State‐Level Risk Assessment in the United States: Making Decisions in the Absence of Federal Risk Values

State environmental agencies in the United States are charged with making risk management decisions that protect public health and the environment while managing limited technical, financial, and human resources. Meanwhile, the federal risk assessment community that provides risk assessment guidance to state agencies is challenged by the rapid growth of the global chemical inventory. When chemical toxicity profiles are unavailable on the U.S. Environmental Protection Agency's Integrated Risk Information System or other federal resources, each state agency must act independently to identify and select appropriate chemical risk values for application in human health risk assessment. This practice can lead to broad interstate variation in the toxicity values selected for any one chemical. Within this context, this article describes the decision‐making process and resources used by the federal government and individual U.S. states. The risk management of trichloroethylene (TCE) in the United States is presented as a case study to demonstrate the need for a collaborative approach among U.S. states toward identification and selection of chemical risk values while awaiting federal risk values to be set. The regulatory experience with TCE is contrasted with collaborative risk science models, such as the European Union's efforts in risk assessment harmonization. Finally, we introduce State Environmental Agency Risk Collaboration for Harmonization, a free online interactive tool designed to help to create a collaborative network among state agencies to provide a vehicle for efficiently sharing information and resources, and for the advancement of harmonization in risk values used among U.S. states when federal guidance is unavailable.     

The Role of Cancer Risk in the Regulation of Industrial Pollution

The extent of carcinogen regulation under existing U.S. environmental statutes is assessed by developing measures of the scope and stringency of regulation. While concern about cancer risk has played an important political role in obtaining support for pollution control programs, it has not provided the predominant rationale for most regulatory actions taken to date. Less than 20% of all standards established to limit concentrations of chemicals in various media address carcinogens. Restrictions on chemical use are more frequently based on concerns about noncancer human health or ecological effects. Of the chemicals in commercial use which have been identified as potential human carcinogens on the basis of rodent bioassays, only a small proportion are regulated. There is an inverse relationship between the scope of regulatory coverage and the stringency of regulatory requirements: the largest percentages of identified carcinogens are affected by the least stringent requirements, such as information disclosure. Standards based on de minimis cancer risk levels have been established for only 10% of identified carcinogens and are restricted to one medium: water. Complete bans on use have affected very few chemicals. The general role that carcinogenicity now plays in the regulatory process is not dramatically different from that of other adverse human health effects: if a substance is identified as a hazard, it may eventually be subject to economically achievable and technically feasible restrictions.     

Analyzing BSE Transmission to Quantify Regional Risk

As a result of consumer fears and political concerns related to BSE as a risk to human health, a need has arisen recently for more sensitive methods to detect BSE and more accurate methods to determine BSE incidence. As a part of the development of such methods, it is important to be able to identify groups of animals with above-average BSE risk. One of the well-known risk factors for BSE is age, as very young animals do not develop the disease, and very old animals are less likely to develop the disease. Here, we analyze which factors have a strong influence on the age distribution of BSE in a population. Building on that, we develop a simple set of calculation rules for classifying the BSE risk in a given cattle population. Required inputs are data on imports and on the BSE control measures in place over the last 10 or 20 years.     

Why Reduced-Form Regression Models of Health Effects Versus Exposures Should Not Replace QRA: Livestock Production and Infant Mortality as an Example

Do pollution emissions from livestock operations increase infant mortality rate (IMR)? A recent regression analysis of changes in IMR against changes in aggregate “animal units” (a weighted sum of cattle, pig, and poultry numbers) over time, for counties throughout the United States, suggested the provocative conclusion that they do: “[A] doubling of production leads to a 7.4% increase in infant mortality.” Yet, we find that regressing IMR changes against changes in specific components of “animal units” (cattle, pigs, and broilers) at the state level reveals statistically significant negative associations between changes in livestock production (especially, cattle production) and changes in IMR. We conclude that statistical associations between livestock variables and IMR variables are very sensitive to modeling choices (e.g., selection of explanatory variables, and use of specific animal types vs. aggregate “animal units). Such associations, whether positive or negative, do not warrant causal interpretation. We suggest that standard methods of quantitative risk assessment (QRA), including emissions release (source) models, fate and transport modeling, exposure assessment, and dose-response modeling, really are important—and indeed, perhaps, essential—for drawing valid causal inferences about health effects of exposures to guide sound, well-informed public health risk management policy. Reduced-form regression models, which skip most or all of these steps, can only quantify statistical associations (which may be due to model specification, variable selection, residual confounding, or other noncausal factors). Sound risk management requires the extra work needed to identify and model valid causal relations.