Weight of evidence evaluation for chemical-induced immunotoxicity for PFOA and PFOS: findings from an independent panel of experts.

Immunotoxicity is the critical endpoint used by some regulatory agencies to establish toxicity values for perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). However, the hypothesis that exposure to certain per- and polyfluoroalkyl substances (PFAS) causes immune dysregulation is subject to much debate. An independent, international expert panel was engaged utilizing methods to reduce bias and "groupthink". The panel concluded there is moderate evidence that PFOS and PFOA are immunotoxic, based primarily on evidence from animal data. However, species concordance and human relevance cannot be well established due to data limitations. The panel recommended additional testing that includes longer-term exposures, evaluates both genders, includes other species of animals, tests lower dose levels, assesses more complete measures of immune responses, and elucidates the mechanism of action. Panel members agreed that the Faroe Islands cohort data should not be used as the primary basis for deriving PFAS risk assessment values. The panel agreed that vaccine antibody titer is not useful as a stand-alone metric for risk assessment. Instead, PFOA and PFOS toxicity values should rely on multiple high-quality studies, which are currently not available for immune suppression. The panel concluded that the available PFAS immune epidemiology studies suffer from weaknesses in study design that preclude their use, whereas available animal toxicity studies provide comprehensive dataset to derive points of departure (PODs) for non-immune endpoints. The panel recommends accounting for potential PFAS immunotoxicity by applying a database uncertainty factor to POD values derived from animal studies for other more robustly supported critical effects.

Longer-duration uses of tetracyclines and penicillins in U.S. food-producing animals: Indications and microbiologic effects.

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.