The fitness cost of horizontally transferred and mutational antimicrobial resistance in Escherichia coli.

Antimicrobial resistance (AMR) in bacteria implies a tradeoff between the benefit of resistance under antimicrobial selection pressure and the incurred fitness cost in the absence of antimicrobials. The fitness cost of a resistance determinant is expected to depend on its genetic support, such as a chromosomal mutation or a plasmid acquisition, and on its impact on cell metabolism, such as an alteration in an essential metabolic pathway or the production of a new enzyme. To provide a global picture of the factors that influence AMR fitness cost, we conducted a systematic review and meta-analysis focused on a single species, Escherichia coli. By combining results from 46 high-quality studies in a multilevel meta-analysis framework, we find that the fitness cost of AMR is smaller when provided by horizontally transferable genes such as those encoding beta-lactamases, compared to mutations in core genes such as those involved in fluoroquinolone and rifampicin resistance. We observe that the accumulation of acquired AMR genes imposes a much smaller burden on the host cell than the accumulation of AMR mutations, and we provide quantitative estimates of the additional cost of a new gene or mutation. These findings highlight that gene acquisition is more efficient than the accumulation of mutations to evolve multidrug resistance, which can contribute to the observed dominance of horizontally transferred genes in the current AMR epidemic.

Aggregate and cumulative chronic risk assessment for pyrethroids in the French adult population.

Pyrethroids are commonly used as insecticides in households, in agriculture or in veterinary and medicinal products. This study aimed to assess cumulative aggregate exposure to cyfluthrin, cypermethrin, deltamethrin and permethrin in adults in France and the associated health risk, and to identify major contributions of exposure sources and routes. External chronic exposures were estimated from dietary and several environmental sources for the oral, inhalation and dermal routes. Internal concentrations of five associated metabolites were simulated with a physiologically-based pharmacokinetic model. The predicted urinary concentrations were in same order of magnitude as those of the French ENNS biomonitoring survey. Dietary exposure, especially from cereals and animal products, was the major source of exposure. For the 1% of adults most highly exposed, dermal exposure to permethrin through medicinal and veterinary products was an important source of exposure. Considering alterations of motor, sensory and autonomic division, all individual margins of exposure were higher than 100, suggesting that no neurotoxic risk associated with the cumulative aggregate exposure to these four pyrethroids is expected for the French adult population.

Cumulative dietary risk assessment overarching different regulatory silos using a margin of exposure approach: A case study with three chemical silos.

Risk assessment of chemicals occurring in our diet is commonly performed for single chemicals without considering exposure to other chemicals. We performed a case study on risk assessment of combined dietary exposure to chemicals from different regulatory silos, i.e. pesticides (PPRs), persistent organic pollutants (POPs) and food additives (FAs). Chemicals were grouped into the cumulative assessment group (CAG) liver steatosis using a component-based approach. Based on literature, the CAG included 144 PPRs, 49 POPS and 7 FAs for which concentration data were available. For each silo, chronic combined dietary exposure was assessed for adults and children of nine European countries following the most commonly used exposure methodologies in Europe and by using a relative potency factor approach. For risk characterization, a Margin of Exposure (MOE) was calculated. To overarch the risk across silos, a normalised combined margin of exposure (nMOET) approach was proposed. This case study demonstrated that risk assessment of combined exposure to chemicals can be performed within regulatory silos. It also highlighted important differences in the conservatism of exposure scenarios, the derivation of point of departures and the subsequent acceptable MOEs between the silos. To overarch the risk despite these differences, a nMOET approach can be used.

Combining data from heterogeneous surveys for aggregate exposure: Application to children exposure to lead in France.

To assess human health risks related to the environment, it is necessary to aggregate exposure from multiple sources. The objective of this paper was to propose a relevant approach to combine data from heterogeneous populations and methodologies. Five different methods based on Monte-Carlo simulations were tested and compared. Differences were: taking into account or not stratification variable, timeline to assign exposure factors and concentration and way to account for concentration correlations. The methods were applied to estimate lead exposure from food, dust, soil, air, and tap water or French children aged between six months and three years old. Comparing results' uncertainty, it is recommended to 1) select a reference population representative of the target population, 2) select stratification variables to combine surveys, and 3) simulate a new population by randomly sampling individuals in the reference population and simultaneously assigning human exposure factors and environmental concentrations from other surveys in integrating correlations (MC1S). No difference was observed when taking into account correlations using vectors of determinist data from one survey or rank of correlations with the Iman-Conover method. Regardless the methods used to combine data, dust was the main exposure source, followed by soil and in a less extent by food. Exposures from air and tap water were found to be insignificant for most children.

Selecting mixtures on the basis of dietary exposure and hazard data: application to pesticide exposure in the European population in relation to steatosis.

Populations are exposed to mixtures of pesticides through their diet on a daily basis. The question of which substances should be assessed together remains a major challenge due to the complexity of the mixtures. In addition, the associated risk is difficult to characterise. The EuroMix project (European Test and Risk Assessment Strategies for Mixtures) has developed a strategy for mixture risk assessment. In particular, it has proposed a methodology that combines exposures and hazard information to identify relevant mixtures of chemicals belonging to any cumulative assessment group (CAG) to which the European population is exposed via food. For the purposes of this study, food consumption and pesticide residue data in food and drinking water were obtained from national surveys in nine European countries. Mixtures of pesticides were identified by a sparse non-negative matrix underestimation (SNMU) applied to the specific liver steatosis effect in children from 11 to 15 years of age, and in adults from 18 to 64 years of age in nine European countries. Exposures and mixtures of 144 pesticides were evaluated through four different scenarios: (1) chronic exposure with a merged concentration dataset in the adult population, (2) chronic exposure with country-specific concentration datasets in the adult population, (3) acute exposure with a merged concentration dataset in the adult population, and (4) chronic exposure with a merged concentration dataset in the paediatric population. The relative potency factors of each substance were calculated to express their potency relative to flusilazole, which was chosen as the reference compound. The selection of mixtures and the evaluation of exposures for each country were carried out using the Monte Carlo Risk Assessment (MCRA) software. Concerning chronic exposure, one mixture explained the largest proportion of the total variance for each country, while in acute exposure, several mixtures were often involved. The results showed that there were 15 main pesticides in the mixtures, with a high contribution of imazalil and dithiocarbamate. Since the concentrations provided by the different countries were merged in the scenario using merged concentration data, differences between countries result from differences in food consumption behaviours. These results support the approach that using merged concentration data to estimate exposures in Europe seems to be realistic, as foods are traded across European borders. The originality of the proposed approach was to start from a CAG and to integrate information from combined exposures to identify a refined list of mixtures with fewer components. As this approach was sensitive to the input data and required significant resources, efforts should continue regarding data collection and harmonisation among the different aspects within the pesticides regulatory framework, and to develop methods to group substances and mixtures to characterise the risk.