Re-evaluation of the existing health-based guidance values for copper and exposure assessment from all sources.

Copper is an essential micronutrient and also a regulated product used in organic and in conventional farming pest management. Both deficiency and excessive exposure to copper can have adverse health effects. In this Scientific Opinion, the EFSA 2021 harmonised approach for establishing health-based guidance values (HBGVs) for substances that are regulated products and also nutrients was used to resolve the divergent existing HBGVs for copper. The tightly regulated homeostasis prevents toxicity manifestation in the short term, but the development of chronic copper toxicity is dependent on copper homeostasis and its tissue retention. Evidence from Wilson disease suggests that hepatic retention is indicative of potential future and possibly sudden onset of copper toxicity under conditions of continuous intake. Hence, emphasis was placed on copper retention as an early marker of potential adverse effects. The relationships between (a) chronic copper exposure and its retention in the body, particularly the liver, and (b) hepatic copper concentrations and evidence of toxicity were examined. The Scientific Committee (SC) concludes that no retention of copper is expected to occur with intake of 5 mg/day and established an Acceptable Daily Intake (ADI) of 0.07 mg/kg bw. A refined dietary exposure assessment was performed, assessing contribution from dietary and non-dietary sources. Background copper levels are a significant source of copper. The contribution of copper from its use as plant protection product (PPP), food and feed additives or fertilisers is negligible. The use of copper in fertilisers or PPPs contributes to copper accumulation in soil. Infant formula and follow-on formula are important contributors to dietary exposure of copper in infants and toddlers. Contribution from non-oral sources is negligible. Dietary exposure to total copper does not exceed the HBGV in adolescents, adults, elderly and the very elderly. Neither hepatic copper retention nor adverse effects are expected to occur from the estimated copper exposure in children due to higher nutrient requirements related to growth.

Guidance on the use of the benchmark dose approach in risk assessment.

The Scientific Committee (SC) reconfirms that the benchmark dose (BMD) approach is a scientifically more advanced method compared to the no-observed-adverse-effect-level (NOAEL) approach for deriving a Reference Point (RP). The major change compared to the previous Guidance (EFSA SC, 2017) concerns the Section 2.5, in which a change from the frequentist to the Bayesian paradigm is recommended. In the former, uncertainty about the unknown parameters is measured by confidence and significance levels, interpreted and calibrated under hypothetical repetition, while probability distributions are attached to the unknown parameters in the Bayesian approach, and the notion of probability is extended to reflect uncertainty of knowledge. In addition, the Bayesian approach can mimic a learning process and reflects the accumulation of knowledge over time. Model averaging is again recommended as the preferred method for estimating the BMD and calculating its credible interval. The set of default models to be used for BMD analysis has been reviewed and amended so that there is now a single set of models for quantal and continuous data. The flow chart guiding the reader step-by-step when performing a BMD analysis has also been updated, and a chapter comparing the frequentist to the Bayesian paradigm inserted. Also, when using Bayesian BMD modelling, the lower bound (BMDL) is to be considered as potential RP, and the upper bound (BMDU) is needed for establishing the BMDU/BMDL ratio reflecting the uncertainty in the BMD estimate. This updated guidance does not call for a general re-evaluation of previous assessments where the NOAEL approach or the BMD approach as described in the 2009 or 2017 Guidance was used, in particular when the exposure is clearly lower (e.g. more than one order of magnitude) than the health-based guidance value. Finally, the SC firmly reiterates to reconsider test guidelines given the wide application of the BMD approach.

Guidance on aneugenicity assessment.

The EFSA Scientific Committee was asked to provide guidance on the most appropriate in vivo tests to follow up on positive in vitro results for aneugenicity, and on the approach to risk assessment for substances that are aneugenic but not clastogenic nor causing gene mutations. The Scientific Committee confirmed that the preferred approach is to perform an in vivo mammalian erythrocyte micronucleus test with a relevant route of administration. If this is positive, it demonstrates that the substance is aneugenic in vivo. A negative result with evidence that the bone marrow is exposed to the test substance supports a conclusion that aneugenic activity is not expressed in vivo. If there is no evidence of exposure to the bone marrow, a negative result is viewed as inconclusive and further studies are required. The liver micronucleus assay, even though not yet fully validated, can provide supporting information for substances that are aneugenic following metabolic activation. The gastrointestinal micronucleus test, conversely, to be further developed, may help to assess aneugenic potential at the initial site of contact for substances that are aneugenic in vitro without metabolic activation. Based on the evidence in relation to mechanisms of aneugenicity, the Scientific Committee concluded that, in principle, health-based guidance values can be established for substances that are aneugenic but not clastogenic nor causing gene mutations, provided that a comprehensive toxicological database is available. For situations in which the toxicological database is not sufficient to establish health-based guidance values, some approaches to risk assessment are proposed. The Scientific Committee recommends further development of the gastrointestinal micronucleus test, and research to improve the understanding of aneugenicity to support risk assessment.

Presymptomatic transmission of SARS-CoV-2 infection: a secondary analysis using published data.

OBJECTIVE: To estimate the proportion of presymptomatic transmission of SARS-CoV-2 infection that can occur, and the timing of transmission relative to symptom onset. SETTING/DESIGN: Secondary analysis of international published data. DATA SOURCES: Meta-analysis of COVID-19 incubation period and a rapid review of serial interval and generation time, which are published separately. PARTICIPANTS: Data from China, the Islamic Republic of Iran, Italy, Republic of Korea, Singapore and Vietnam from December 2019 to May 2020. METHODS: Simulations were generated of incubation period and of serial interval or generation time. From these, transmission times relative to symptom onset, and the proportion of presymptomatic transmission, were estimated. OUTCOME MEASURES: Transmission time of SARS-CoV-2 relative to symptom onset and proportion of presymptomatic transmission. RESULTS: Based on 18 serial interval/generation time estimates from 15 papers, mean transmission time relative to symptom onset ranged from -2.6 (95% CI -3.0 to -2.1) days before infector symptom onset to 1.4 (95% CI 1.0 to 1.8) days after symptom onset. The proportion of presymptomatic transmission ranged from 45.9% (95% CI 42.9% to 49.0%) to 69.1% (95% CI 66.2% to 71.9%). CONCLUSIONS: There is substantial potential for presymptomatic transmission of SARS-CoV-2 across a range of different contexts. This highlights the need for rapid case detection, contact tracing and quarantine. The transmission patterns that we report reflect the combination of biological infectiousness and transmission opportunities which vary according to context.

Relative infectiousness of asymptomatic SARS-CoV-2 infected persons compared with symptomatic individuals: a rapid scoping review.

OBJECTIVES: The aim of this study was to determine the relative infectiousness of asymptomatic SARS-CoV-2 infected persons compared with symptomatic individuals based on a scoping review of available literature. DESIGN: Rapid scoping review of peer-reviewed literature from 1 January to 5 December 2020 using the LitCovid database and the Cochrane library. SETTING: International studies on the infectiousness of individuals infected with SARS-CoV-2. PARTICIPANTS: Studies were selected for inclusion if they defined asymptomatics as a separate cohort distinct from presymptomatics and if they provided a quantitative measure of the infectiousness of asymptomatics relative to symptomatics. PRIMARY OUTCOME MEASURES: PCR result (PCR studies), the rate of infection (mathematical modelling studies) and secondary attack rate (contact tracing studies) - in each case from asymptomatic in comparison with symptomatic individuals. RESULTS: There are only a limited number of published studies that report estimates of relative infectiousness of asymptomatic compared with symptomatic individuals. 12 studies were included after the screening process. Significant differences exist in the definition of infectiousness. PCR studies in general show no difference in shedding levels between symptomatic and asymptomatic individuals; however, the number of study subjects is generally limited. Two modelling studies estimate relative infectiousness to be 0.43 and 0.57, but both of these were more reflective of the infectiousness of undocumented rather than asymptomatic cases. The results from contact tracing studies include estimates of relative infectiousness of 0, but with insufficient evidence to conclude that it is significantly different from 1. CONCLUSIONS: There is considerable heterogeneity in estimates of relative infectiousness highlighting the need for further investigation of this important parameter. It is not possible to provide any conclusive estimate of relative infectiousness, as the estimates from the reviewed studies varied between 0 and 1.

Guidance Document on Scientific criteria for grouping chemicals into assessment groups for human risk assessment of combined exposure to multiple chemicals.

This guidance document provides harmonised and flexible methodologies to apply scientific criteria and prioritisation methods for grouping chemicals into assessment groups for human risk assessment of combined exposure to multiple chemicals. In the context of EFSA's risk assessments, the problem formulation step defines the chemicals to be assessed in the terms of reference usually through regulatory criteria often set by risk managers based on legislative requirements. Scientific criteria such as hazard-driven criteria can be used to group these chemicals into assessment groups. In this guidance document, a framework is proposed to apply hazard-driven criteria for grouping of chemicals into assessment groups using mechanistic information on toxicity as the gold standard where available (i.e. common mode of action or adverse outcome pathway) through a structured weight of evidence approach. However, when such mechanistic data are not available, grouping may be performed using a common adverse outcome. Toxicokinetic data can also be useful for grouping, particularly when metabolism information is available for a class of compounds and common toxicologically relevant metabolites are shared. In addition, prioritisation methods provide means to identify low-priority chemicals and reduce the number of chemicals in an assessment group. Prioritisation methods include combined risk-based approaches, risk-based approaches for single chemicals and exposure-driven approaches. Case studies have been provided to illustrate the practical application of hazard-driven criteria and the use of prioritisation methods for grouping of chemicals in assessment groups. Recommendations for future work are discussed.

Guidance on harmonised methodologies for human health, animal health and ecological risk assessment of combined exposure to multiple chemicals.

This Guidance document describes harmonised risk assessment methodologies for combined exposure to multiple chemicals for all relevant areas within EFSA's remit, i.e. human health, animal health and ecological areas. First, a short review of the key terms, scientific basis for combined exposure risk assessment and approaches to assessing (eco)toxicology is given, including existing frameworks for these risk assessments. This background was evaluated, resulting in a harmonised framework for risk assessment of combined exposure to multiple chemicals. The framework is based on the risk assessment steps (problem formulation, exposure assessment, hazard identification and characterisation, and risk characterisation including uncertainty analysis), with tiered and stepwise approaches for both whole mixture approaches and component-based approaches. Specific considerations are given to component-based approaches including the grouping of chemicals into common assessment groups, the use of dose addition as a default assumption, approaches to integrate evidence of interactions and the refinement of assessment groups. Case studies are annexed in this guidance document to explore the feasibility and spectrum of applications of the proposed methods and approaches for human and animal health and ecological risk assessment. The Scientific Committee considers that this Guidance is fit for purpose for risk assessments of combined exposure to multiple chemicals and should be applied in all relevant areas of EFSA's work. Future work and research are recommended.

Study on the Association between Tail Lesion Score, Cold Carcass Weight, and Viscera Condemnations in Slaughter Pigs.

The aim of this study was to assess the relationship between tail lesions, cold carcass weight, and viscera condemnations in an Irish abattoir. The following data were collected at the evisceration point from every third pig slaughtered over 7 days: farm identification, sex, tail lesion score, viscera inspection outcome, and cold carcass weight. Tail lesions were scored according to a 5-point scale. Disease lesions responsible for lung (pleurisy, pneumonia, and abscess), heart (pericarditis), and liver (ascariasis) condemnation were recorded based on the decision of the veterinary inspector (VI). Data on 3,143 pigs from 61 batches were available. The relationship between disease lesions, tail lesion score, and cold carcass weight was studied at individual carcass level, while the relationship between disease lesions and tail lesion score was studied at both carcass and batch level. Tail lesions (score ≥1) were found in 72% of the study population, with 2.3% affected by severe tail lesions (scores ≥3). Pleurisy (13.7%) followed by pneumonia (10.4%) showed the highest prevalence, whereas the prevalence of ascariasis showed the greatest variation between batches (0-75%). Tail lesion score, pleurisy, pleuropneumonia, and pericarditis were associated with reductions in carcass cold weight (P ≤ 0.05) ranging from 3 to 6.6 kg. Tail lesion score was associated with condemnations for pleurisy, pneumonia, and pleuropneumonia (P ≤ 0.05) at a batch level. VI shift was associated with condemnations for pneumonia, pleuropneumonia, and pericarditis (P ≤ 0.05) at a carcass level and with pneumonia at a batch level. Sex was not associated with viscera condemnations but males were more likely to be affected by tail lesions. The relationship between overall tail lesion score and the lung diseases at batch level supports the relationship between poor health and poor welfare of pigs on farms. The inclusion of tail lesion scores at post-mortem meat inspection should be considered as a health and welfare diagnostic tool.