Observational Dose-Response Meta-Analysis Methods May Bias Risk Estimates at Low Consumption Levels: The Case of Meat and Colorectal Cancer.

Observational studies of foods and health are susceptible to bias, particularly from confounding between diet and other lifestyle factors. Common methods for deriving dose-response meta-analysis (DRMA) may contribute to biased or overly certain risk estimates. We used DRMA models to evaluate the empirical evidence for colorectal cancer (CRC) association with unprocessed red meat (RM) and processed meats (PM), and the consistency of this association for low and high consumers under different modeling assumptions. Using the Global Burden of Disease project's systematic reviews as a start, we compiled a data set of studies of PM with 29 cohorts contributing 23,522,676 person-years and of 23 cohorts for RM totaling 17,259,839 person-years. We fitted DRMA models to lower consumers only [consumption < United States median of PM (21 g/d) or RM (56 g/d)] and compared them with DRMA models using all consumers. To investigate impacts of model selection, we compared classical DRMA models against an empirical model for both lower consumers only and for all consumers. Finally, we assessed if the type of reference consumer (nonconsumer or mixed consumer/nonconsumer) influenced a meta-analysis of the lowest consumption arm. We found no significant association with consumption of 50 g/d RM using an empirical fit with lower consumption (relative risk [RR] 0.93 (0.8-1.02) or all consumption levels (1.04 (0.99-1.10)), while classical models showed RRs as high as 1.09 (1.00-1.18) at 50g/day. PM consumption of 20 g/d was not associated with CRC (1.01 (0.87-1.18)) when using lower consumer data, regardless of model choice. Using all consumption data resulted in association with CRC at 20g/day of PM for the empirical models (1.07 (1.02-1.12)) and with as little as 1g/day for classical models. The empirical DRMA showed nonlinear, nonmonotonic relationships for PM and RM. Nonconsumer reference groups did not affect RM (P = 0.056) or PM (P = 0.937) association with CRC in lowest consumption arms. In conclusion, classical DRMA model assumptions and inclusion of higher consumption levels influence the association between CRC and low RM and PM consumption. Furthermore, a no-risk limit of 0 g/d consumption of RM and PM is inconsistent with the evidence.

Guidelines to restrict consumption of red meat to under 350 g/wk based on colorectal cancer risk are not consistent with health evidence.

BACKGROUND: The Nordic Nutrition Recommendations of 2023 (NNR2023) incorporate sustainability, health, and nutrition in their food-based dietary guidelines (FBDGs). NNR2023 recommends a consumption of ≤350 g/wk of unprocessed red meat (RM) based on association with colorectal cancer (CRC). This recommendation is lower than other FBDGs such as the World Cancer Research Fund (WCRF) recommendation it is based on (350-500 g/wk). OBJECTIVE: To evaluate the empirical evidence and models cited by the NNR2023 to support the RM guidance. METHODS: We fitted least-assumption (LA) dose-response (DR) models to the studies included in two systematic reviews (SRs) selected by NNR2023 on the RM and CRC association. We compared them against six parametric models reported in the two SRs. We evaluated the statistical significance of modeled relative risks (RR) at different consumption levels. RESULTS: Twenty-one studies (20,604,188 patient-years) were analyzed. We found no significant association (RR = 1.04, 0.99-1.09) between 350g/wk of RM and CRC using the LA models, in agreement with the least restrictive models reported by Lescinsky et al., 2022 (RR = 1.11[0.89-1.38]) and WCRF (RR= 1.01[0.96-1.07]). The association was significant at 350 g/wk only under restricting assumptions such as monotonicity RR=1.3[1.01-1.64], and linearity RR = 1.06 [1.00-1.12]. No significant empirical association is observed under 567 g/wk based on evidence used by NNR2023. CONCLUSIONS: The sources cited by NNR2023 do not support a consumption restriction of ≤350 g/wk of RM due to CRC, and other studies omitted by NNR2023 do not support association between RM and CRC. We show that model assumptions rather than empirical evidence drive this recommendation. Model uncertainty should be explicitly incorporated in FBDGs.

The genomic and epidemiological virulence patterns of Salmonella enterica serovars in the United States.

The serovars of Salmonella enterica display dramatic differences in pathogenesis and host preferences. We developed a process (patent pending) for grouping Salmonella isolates and serovars by their public health risk. We collated a curated set of 12,337 S. enterica isolate genomes from human, beef, and bovine sources in the US. After annotating a virulence gene catalog for each isolate, we used unsupervised random forest methods to estimate the proximity (similarity) between isolates based upon the genomic presentation of putative virulence traits We then grouped isolates (virulence clusters) using hierarchical clustering (Ward's method), used non-parametric bootstrapping to assess cluster stability, and externally validated the clusters against epidemiological virulence measures from FoodNet, the National Outbreak Reporting System (NORS), and US federal sampling of beef products. We identified five stable virulence clusters of S. enterica serovars. Cluster 1 (higher virulence) serovars yielded an annual incidence rate of domestically acquired sporadic cases roughly one and a half times higher than the other four clusters combined (Clusters 2-5, lower virulence). Compared to other clusters, cluster 1 also had a higher proportion of infections leading to hospitalization and was implicated in more foodborne and beef-associated outbreaks, despite being isolated at a similar frequency from beef products as other clusters. We also identified subpopulations within 11 serovars. Remarkably, we found S. Infantis and S. Typhimurium subpopulations that significantly differed in genome length and clinical case presentation. Further, we found that the presence of the pESI plasmid accounted for the genome length differences between the S. Infantis subpopulations. Our results show that S. enterica strains associated with highest incidence of human infections share a common virulence repertoire. This work could be updated regularly and used in combination with foodborne surveillance information to prioritize serovars of public health concern.

Codex Alimentarius Guidelines for Risk Analysis of Foodborne Antimicrobial Resistance Are Incompatible with Available Surveillance Data.

ABSTRACT: Foodborne antimicrobial-resistant (AMR) microorganisms are a global food safety concern. Antimicrobial drug use (AMU) in livestock may increase the risk of resistant foodborne bacterial infections in humans via contaminated animal products. Consequently, countries have implemented different livestock AMU restriction policies, opening the potential for trade disputes. AMR risk equivalence between countries with different AMU policies must be established by using scientifically justified risk assessments. The Codex Alimentarius Commission's Guidelines for Risk Analysis of Foodborne Antimicrobial Resistance (AMR Codex) recommends an approach that requires quantification of detailed information, for which, in many instances, little to no data exist. Using AMR Salmonella exposure from beef consumption as an example, we demonstrate the difficulty of implementing the AMR Codex by comparing key regionally specific parameters within the United States and European Union, two regions with substantial beef production and consumption, robust foodborne pathogen sampling and surveillance systems, and different AMU policies. Currently, neither region fully captures data for key regional variables to populate a detailed risk assessment as outlined in the AMR Codex, nor are they able to adequately link AMU in livestock to AMR infections in humans. Therefore, the AMR Codex guidelines are currently aspirational and not a viable option to assess the impact of livestock AMU reductions on the human health risk of AMR salmonellosis from beef or produce regionally comparable estimates of risk. More flexible risk assessment guidelines that more directly link livestock AMU to human health risk and are amenable to currently available data are needed to allow for country variations and to calculate comparable regional risk estimates, which can be used to guide international trade policy.

Partitioning, a Novel Approach to Mitigate the Risk and Impact of African Swine Fever in Affected Areas.

As African swine fever (ASF) continues to expand geographically, supplementary control strategies are needed to reduce disease risk and impact in affected areas. Full depopulation is central to current ASF control efforts, and its efficacy depends on surveillance and timely disease reporting, while resulting in large losses regardless of the producers' efforts to promptly detect, report, and contain the disease. This disconnect between prompt detection and reporting, and subsequent farm losses, can deter producers to invest in ASF detection and control. Alternative approaches are needed to incentivize individual producers to invest in early detection and reporting. We postulate that commercial swine farms may be effectively partitioned in separate units, or subpopulations, to which biosecurity, surveillance and control can be applied. The suggested Partitioning framework relies on three main components: 1. external and internal biosecurity to reduce the risk of ASF introduction and maintain separate subpopulations; 2. cost-effective on-farm ASF surveillance to enhance early detection; 3. response plans at the unit level, including culling of affected subpopulations, and demonstration of freedom from disease on the remaining ones. With such Partitioning approach, individual producers may reduce ASF risk on a farm and in the region, while also reducing ASF outbreak losses via targeted depopulation of affected units. It requires relevant legislation to incorporate the notion of within-farm subpopulations and provide a regulatory framework for targeted depopulation and substantiation of disease freedom. Its design should be tailored to fit individual farms. Partitioning can be an effective public-private partnership approach for ASF risk reduction. It should be driven by industry, as its benefits are accrued mainly by individual producers, but regulatory oversight is key to ensure proper implementation and avoid further disease spread. Partitioning's value is greatest for producers in ASF-affected regions, but ASF-free areas could also benefit from it for preparedness and early detection. It could also be adapted to other transboundary animal diseases and can be implemented as a stand-alone program or in conjunction with other efforts such as zoning and compartmentalization. Partitioning would contribute to the improved resilience and sustainability of the global pork industry and will benefit consumers and society through improved food security and animal welfare.

No Change in Risk for Antibiotic-Resistant Salmonellosis from Beef, United States, 2002-2010.

Restricting antibiotic use in food production animals is a target for reducing antimicrobial drug-resistant infections in humans. We used US surveillance data to estimate the probability of antibiotic-resistant nontyphoidal salmonellosis per meal made with beef during 2002-2010. Applying data for nontyphoidal Salmonella in raised-without-antibiotics cattle, we tested the effect of removing antibiotic use from all beef cattle production. We found an average of 1.2 (95% credible interval 0.6-4.2) antibiotic-resistant nontyphoidal salmonellosis cases per 1 million beef meals made with beef initially contaminated with antibiotic-resistant nontyphoidal Salmonella at slaughter or retail and 0.031 (95% credible interval 0.00018-0.14) cases per 1 million meals irrespective of beef contamination status. Neither outcome showed sustained change except for increases in 2003 and 2009 (>98% confidence) when larger or more outbreaks occurred. Switching all beef production to a raised-without-antibiotics system may not have a significant effect on antibiotic-resistant nontyphoidal salmonellosis (94.3% confidence).

The EAT-Lancet Commission's Dietary Composition May Not Prevent Noncommunicable Disease Mortality.

The recently published EAT-Lancet Commission report on dietary impacts on the environment suggested that their proposed diet could prevent more than 10 million annual premature mortalities from noncommunicable diseases globally. The report did not meet standards for transparency and replicability, nor did it fully account for statistical uncertainty. Our attempt to replicate the mortality calculations for the United States revealed flaws in the assumptions and methods used to estimate the avoided mortalities. After correcting some calculation errors and fully accounting for uncertainty in the avoided mortalities, the mortality reduction effect of the EAT-Lancet proposed diet in the USA is no greater than the impact of energy consumption changes that would prevent under-weight, over-weight, and obesity alone. As our findings call into question the global conclusions of the EAT-Lancet report, futher independent validation is needed before it can be used to inform dietary guidelines.

Probabilistic estimates of heterocyclic amines and polycyclic aromatic hydrocarbons concentrations in meats and breads applicable to exposure assessments.

Random effect meta-regressions were constructed to estimate concentrations of two heterocyclic amines (HCA) and eight polycyclic aromatic hydrocarbons (PAH) in meat and breads. Eighteen HCA studies and nine PAH studies of food concentration were assembled. Concentration was computed for beef, poultry, pork, and seafood, and bread. Fixed effect predictors included cooking time, form of the food, cooking method, interaction between form and cooking method, temperature at which the food was cooked, fuel of the flame source, percentage of fat, and other elements. Meat type was significant to all HCAs but only three of the PAHs. Cooking method or an interaction between cooking method and food form was significant in all the overall models for each compound, and 80% of models created for stratifications of the data based on meat type. Improvement on compilations such as the Computerized Heterocyclic Amines Resource for Research in Epidemiology of Disease (CHARRED) database comes from inclusion of additional studies, PAH compounds, more generalizable food categories, more cooking methods (such as smoking), and addition of seafood. Meta-regression allows parameters to be estimated with separation of between-study heterogeneity, and extrapolation of exposures to more foods. Resulting uncertainty estimates are useful in a probabilistic exposure assessment.

Probabilistic assessment of dietary exposure to heterocyclic amines and polycyclic aromatic hydrocarbons from consumption of meats and breads in the United States.

This probabilistic analysis estimated daily dietary exposures of the US population to heterocyclic amines and polycyclic aromatic hydrocarbons from meat and some varieties of bread. Mean concentrations for these foods grouped by cooking method and food form were combined with consumption data from the National Health and Nutritional Examination Survey (NHANES). Mean exposure to HCA2 (PhIP + MeIQx), was 565.3 ng/day (95% CrI: 403.73, 726.88), and to PAH8 (sum of BaP, ChY, BaA, BkF, BbF, DahA, IP, and BghiP), was 634.8 ng/day (568.38, 701.15). HCA2 exposures were not significantly different between meat types, but multiple differences were found between cooking types. Exposures to PAH8 in the mean consumers differed significantly between cooking methods, and were higher for beef than poultry (mean difference: 983 ng, 95%CrI: -77.0, 4076.0) and pork (990 ng, 95%CrI: 23.7, 4061.8), but not for any other food comparisons. Tradeoffs between exposures associated with a typical portion size of potential food replacements were also examined. Differences in HCA2 and PAH8 exposure are primarily driven by the preparation method rather than the type of meat. These findings should be considered in future studies linking PAH and HCA compounds with human health impacts.

Comparative Probabilistic Assessment of Occupational Pesticide Exposures Based on Regulatory Assessments.

Implementation of probabilistic analyses in exposure assessment can provide valuable insight into the risks of those at the extremes of population distributions, including more vulnerable or sensitive subgroups. Incorporation of these analyses into current regulatory methods for occupational pesticide exposure is enabled by the exposure data sets and associated data currently used in the risk assessment approach of the Environmental Protection Agency (EPA). Monte Carlo simulations were performed on exposure measurements from the Agricultural Handler Exposure Database and the Pesticide Handler Exposure Database along with data from the Exposure Factors Handbook and other sources to calculate exposure rates for three different neurotoxic compounds (azinphos methyl, acetamiprid, emamectin benzoate) across four pesticide-handling scenarios. Probabilistic estimates of doses were compared with the no observable effect levels used in the EPA occupational risk assessments. Some percentage of workers were predicted to exceed the level of concern for all three compounds: 54% for azinphos methyl, 5% for acetamiprid, and 20% for emamectin benzoate. This finding has implications for pesticide risk assessment and offers an alternative procedure that may be more protective of those at the extremes of exposure than the current approach.

Confined space ventilation by shipyard welders: observed use and effectiveness.

Shipbuilding involves intensive welding activities within enclosed and confined spaces, and although ventilation is commonly used in the industry, its use and effectiveness has not been adequately documented. Workers engaged in welding in enclosed or confined spaces in two shipyards were observed for their use of ventilation and monitored for their exposure to particulate matter. The type of ventilation in use, its placement and face velocity, the movement of air within the space, and other ventilation-related parameters were recorded, along with task characteristics such as the type of welding, the welder's position, and the configuration of the space. Mechanical ventilation was present in about two-thirds of the 65 welding scenarios observed, with exhaust ventilation used predominantly in one shipyard and supply blowers predominantly in the other. Welders were observed working in apparent dead-spaces within the room in 53% of the cases, even where ventilation was in use. Respiratory protection was common in the two shipyards, observed in use in 77 and 100% of the cases. Welding method, the proximity of the welder's head to the fume, and air mixing were found to be significantly associated with the welder's exposure, while other characteristics of dilution ventilation did not produce appreciable differences in exposure level. These parameters associated with exposure reduction can be assessed subjectively and are thus good candidates for training on effective ventilation use during hot work in confined spaces. Ventilation used in confined space welding is often inadequate for controlling exposure to welding fume.