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Denver, CO, United States

Mathers J.J.,Alpharma LLC | Flick S.C.,Alpharma LLC | Cox L.A.,Cox Associates
Environment International

We review and analyze regulatory categories for longer duration of use (defined as ≥ 7. day) tetracyclines (TCs) and penicillins (PNs) approved for U.S. livestock and poultry, together with scientific studies, surveillance programs and risk assessments pertaining to antimicrobial resistance. Indications listed on a government database were grouped into three broad categories according to the terminology used to describe their use: disease control (C), treatment (T) and growth improvement (G). Consistent with mostly therapeutic uses, the majority (86%) of listed indications had C and/or T terms. Several studies showed interruption of early disease stages in animals and modulation of intestinal microflora. Longer-duration exposures are consistent with bacteriostatic modes of action, where adequate exposure time as well as concentration is needed for sufficient antimicrobial activity. Other effects identified included reduced animal pathogen prevalence, toxin formation, inflammation, environmental impacts, improved animal health, reproductive measures, nutrient utilization, and others. Several animal studies have shown a limited, dose-proportionate, selective increase in resistance prevalence among commensal animal bacteria following longer-duration exposures. Pathogen surveillance programs showed overall stable or declining resistance trends among sentinel bacteria. Quantitative, microbiologically detailed resistance risk assessments indicate small probabilities of human treatment failure due to resistance under current conditions. Evaluations of longer-duration uses of TCs, PNs, and other antimicrobial classes used in food-producing animals should consider mechanisms of activity, known individual- and population-level health and waste reduction effects in addition to resistance risks. © 2011 Elsevier Ltd. Source

Cox L.A.,Cox Associates | Cox L.A.,University of Colorado at Denver | Van Orden D.R.,RJ Lee Group, Inc | Lee R.J.,RJ Lee Group, Inc | And 5 more authors.
Regulatory Toxicology and Pharmacology

To determine how reliably commercial laboratories measure crystalline silica concentrations corresponding to OSHA's proposed limits, 105 filters were prepared with known masses of 20, 40, and 80μg ofrespirable quartz corresponding to airborne silica concentrations of 25, 50, and 100 μg/m3 and were submitted, in a blind test, to qualified commercial laboratories over a nine month period. Under these test conditions, the reported results indicated a lack of accuracy and precision needed to reliably inform regulatory compliance decisions. This was true even for filters containing only silica, without an interfering matrix. For 36 filters loaded with 20 or more micrograms of silica, the laboratories reported non-detected levels of silica. Inter-laboratory variability in this performance test program was so high that the reported results could not be used to reliably discriminate among filters prepared to reflect 8-hexposures to respirable quartz concentrations of 25, 50 and 100μg/m3. Moreover, even in intra-laboratory performance, there was so much variability in the reported results that 2-fold variations in exposure concentrations could not be reliably distinguished. Part of the variability and underreporting may result from the sample preparation process. The results of this study suggest that current laboratory methods and practices cannot necessarily be depended on, with high confidence, to support proposed regulatory standards with reliable data. © 2015 Elsevier Inc. Source

Popken D.A.,Cox Associates | Cox L.A.,Jr.
Human and Ecological Risk Assessment

ABSTRACT: Open livestock production systems,including free-range and organic livestock systems,seek to improve the welfare of animals by letting them roam in unconfined spaces. This increases their exposure to potentially harmful micro-organisms. For example,swine in open production systems have a much greater risk of Toxoplasma gondii infection. When transmitted through the food chain,T. gondii threatens human health,especially in unborn children of women infected during pregnancy,as well as the lives of patients with compromised immune systems. By contrast,conventional total confinement production systems can now keep this human health risk at or near zero. This article describes a probabilistic risk simulation model that quantified the tradeoff between greater use of open swine production systems and increased cases of toxoplasmosis in humans. The model predicts that every 1804 pigs shifted from conventional total confinement to open production(95% confidence interval 747–9520) would cause the loss of one additional human quality-adjusted life year(QALY),and that increasing the fraction of U.S. swine raised in open/free range operations by 0.1%(approx. 65,000 pigs) would cause a loss of approximately 36 human QALYs per year,including between 1 and 2 extra adult deaths per year. © 2015,Copyright © Taylor & Francis Group,LLC. Source

Whether crystalline silica (CS) exposure increases risk of lung cancer in humans without silicosis, and, if so, whether the exposure-response relation has a threshold, have been much debated. Epidemiological evidence is ambiguous and conflicting. Experimental data show that high levels of CS cause lung cancer in rats, although not in other species, including mice, guinea pigs, or hamsters; but the relevance of such animal data to humans has been uncertain. This article applies recent insights into the toxicology of lung diseases caused by poorly soluble particles (PSPs), and by CS in particular, to model the exposure-response relation between CS and risk of lung pathologies such as chronic inflammation, silicosis, fibrosis, and lung cancer. An inflammatory mode of action is described, having substantial empirical support, in which exposure increases alveolar macrophages and neutrophils in the alveolar epithelium, leading to increased reactive oxygen species (ROS) and nitrogen species (RNS), pro-inflammatory mediators such as TNF-alpha, and eventual damage to lung tissue and epithelial hyperplasia, resulting in fibrosis and increased lung cancer risk among silicotics. This mode of action involves several positive feedback loops. Exposures that increase the gain factors around such loops can create a disease state with elevated levels of ROS, TNF-alpha, TGF-beta, alveolar macrophages, and neutrophils. This mechanism implies a "tipping point" threshold for the exposure-response relation. Applying this new model to epidemiological data, we conclude that current permissible exposure levels, on the order of 0.1 mg/m 3, are probably below the threshold for triggering lung diseases in humans. © 2011 Society for Risk Analysis. Source

Cox L.A.,Cox Associates | Popken D.,Cox Associates | Marty M.S.,Dow Chemical Company | Rowlands J.C.,Dow Chemical Company | And 3 more authors.
Regulatory Toxicology and Pharmacology

High throughput (HTS) and high content (HCS) screening methods show great promise in changing how hazard and risk assessments are undertaken, but scientific confidence in such methods and associated prediction models needs to be established prior to regulatory use. Using a case study of HTS-derived models for predicting in vivo androgen (A), estrogen (E), thyroid (T) and steroidogenesis (S) endpoints in endocrine screening assays, we compare classification (fitting) models to cross validation (prediction) models. The more robust cross validation models (based on a set of endocrine ToxCast™ assays and guideline in vivo endocrine screening studies) have balanced accuracies from 79% to 85% for A and E, but only 23% to 50% for T and S. Thus, for E and A, HTS results appear promising for initial use in setting priorities for endocrine screening. However, continued research is needed to expand the domain of applicability and to develop more robust HTS/HCS-based prediction models prior to their use in other regulatory applications. Based on the lessons learned, we propose a framework for documenting scientific confidence in HTS assays and the prediction models derived therefrom. The documentation, transparency and the scientific rigor involved in addressing the elements in the proposed Scientific Confidence Framework could aid in discussions and decisions about the prediction accuracy needed for different applications. © 2014 The Authors. Source

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