Understanding the transfer of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) as well as polychlorinated biphenyls (PCBs) from oral exposure into cow’s milk is not purely an experimental endeavour, as it has produced a large corpus of theoretical work. This work consists of a variety of predictive toxicokinetic models in the realms of health and environmental risk assessment and risk management. Their purpose is to provide mathematical predictive tools to organise and integrate knowledge on the absorption, distribution, metabolism and excretion processes. Toxicokinetic models are based on more than 50 years of transfer studies summarised in part I of this review series. Here in part II, several of these models are described and systematically classified with a focus on their applicability to risk analysis as well as their limitations. This part of the review highlights the opportunities and challenges along the way towards accurate, congener-specific predictive models applicable to changing animal breeds and husbandry conditions.

Polychlorinated dibenzo-para-dioxins (PCDDs) and dibenzofurans (PCDFs) (collectively and colloquially referred to as ‘dioxins’) as well as polychlorinated biphenyls (PCBs) are persistent and ubiquitous environmental contaminants that may unintentionally enter and accumulate along the food chain. Owing to their chronic toxic effects in humans and bioaccumulative properties, their presence in feed and food requires particular attention. One important exposure pathway for consumers is consumption of milk and dairy products. Their transfer from feed to milk has been studied for the past 50 years to quantify the uptake and elimination kinetics. We extracted transfer parameters (transfer rate, transfer factor, biotransfer factor and elimination half-lives) in a machine-readable format from seventy-six primary and twenty-nine secondary literature items. Kinetic data for some toxicologically relevant dioxin congeners and the elimination half-lives of dioxin-like PCBs are still not available. A well-defined selection of transfer parameters from literature was statistically analysed and shown to display high variability. To understand this variability, we discuss the data with an emphasis on influencing factors, such as experimental conditions, cow performance parameters and metabolic state. While no universal interpretation could be derived, a tendency for increased transfer into milk is apparently connected to an increase in milk yield and milk fat yield as well as during times of body fat mobilisation, for example during the negative energy balance after calving. Over the past decades, milk yield has increased to over 40 kg/d during high lactation, so more research is needed on how this impacts feed to food transfer for PCDD/Fs and PCBs.

As a consequence of the toxicological lead characteristics, a reduction of its exposure should consider all sources. Game meat might contain elevated levels of lead due to the use of lead ammunition. The aim of the present study was to investigate the effects of acidic marination on the bioavailability of ammunition-derived lead in game meat (Roe deer), using the growing pig as an animal model. Furthermore, the study should provide evidence that the large-area scattering of lead particles leads to noticeable differences in the individual lead intake per game meat portion. Pigs of group A (n 7) received lead-shot game meat, which was cooked in water. Pigs of group B (n 7) received lead-shot game meat, which was first marinated (wine and vinegar) and then cooked. The lead content of both game meat preparations was equal with 0⋅77–0⋅79 mg Pb/portion. Pigs of group C (n 4) received lead-free game meat, which was also marinated and cooked. Additionally, lead acetate was administered intravenously to group D pigs (n 4). Blood samples were taken on elevated time points before and after game meat intake/i.v.-application. The acidic marination increased the bioavailability of orally ingested lead, resulting in significantly higher blood lead concentrations. The bioavailability of lead was 2⋅7 % when game meat was just cooked and 15 % when the meat was marinated before. The considerable variation of the individual blood lead concentrations suggests that an inhomogeneous distribution of ammunition-derived lead particles (in terms of size and number) causes individually non-comparable lead intakes from the consumption of game meat.

ABSTRACT IMPACT: Findings from this study will better characterize the role of hearing loss in falls risk among patients with vestibulopathy and identify groups that are most at risk for falls. OBJECTIVES/GOALS: Vestibular dysfunction and hearing loss are independent risk factors for experiencing falls. The purpose of this study is to determine the extent, if any, to which hearing loss contributes to falls in patients with concomitant vestibular dysfunction presenting to a specialty vestibular clinic. METHODS/STUDY POPULATION: A retrospective chart review of patients ≥18 years who underwent vestibular evaluation at our institution from June 1, 2015 to October 7, 2020 will be conducted. Patients who underwent vestibular evaluation also received audiologic evaluation and degree of hearing loss will be characterized by the 4-frequency pure-tone average (0.5, 1, 2, and 4 kHz) of the better hearing ear. Falls status will be determined by the response to the following question administered at clinic-check in, ‘Have you fallen in the last 90 days?’ Demographics, comorbidities, and falls-associated medications will also be collected. RESULTS/ANTICIPATED RESULTS: A total of 3,265 unique patients who underwent vestibular evaluation in the study time period were identified. Patients will be categorized into discrete groups (benign paroxysmal positional vertigo, unilateral hypofunction, bilateral hypofunction, central dysfunction, and normal) based on laboratory results. Regression models will be developed to evaluate the potential association between degree of hearing loss and falls in patients with different types of vestibular dysfunction, while adjusting for demographics, comorbidities, and falls-associated medications. DISCUSSION/SIGNIFICANCE OF FINDINGS: Findings from this study will better characterize the role of hearing loss in falls risk among patients with vestibulopathy and identify groups that are most at risk for falls. This study may potentially indicate the importance of hearing evaluation in the work-up of patients with vestibulopathy.

This research communication describes (1) the comparison of acute-phase protein (APP) concentrations in transition dairy cows on different farms using both pooled and individual blood samples, and (2) the association among different APP and clinical health parameters. The first hypothesis was that early postpartum dairy cows from different farms differ in the level of inflammation, which might be determined using APP assays in both pooled and individual blood samples. The second hypothesis was that the APP haptoglobin (Hp) might be the most sensitive parameter to detect cows at risk of excessive postpartum inflammation concomitant with systemic disease. Serum concentrations of Hp, serum amyloid-A (SAA), total protein (TP), albumin (Alb), coeruloplasmin (Cp) and C-reactive protein (CRP) in 100 fresh lactating cows (within 0–8 d postpartum) from 10 farms were compared and associated to clinical health parameters (rectal body temperature, vaginal discharge (Metricheck™ score), rumen fill, vulvovaginal laceration) using both pooled and individual blood samples. Mean serum concentrations of Hp, SAA and TP revealed significant differences among farms. Pooled serum samples of farms showed high correlations with the mean of individual samples. Only Hp was significantly positively correlated to both body temperature and Metricheck™ score. In conclusion, Hp differentiates dairy farms regarding the inflammatory state of transition cows using individual and pooled serum samples within the first week postpartum. It also mirrors the individual degree of inflammation, thus proving to be a diagnostic parameter of high interest during the periparturient period.

Zn serves as a powerful feed additive to reduce post-weaning diarrhoea in pigs. However, the mechanisms responsible for Zn-associated effects on the adaptive immune responses following feeding of a very high dosage of Zn remain elusive. In this study, we examined the T-cell response in gut-associated lymphatic tissues of seventy-two weaned piglets. Piglets received diets with 57 mg Zn/kg (low Zn concentration, LZn), 164 mg Zn/kg (medium Zn concentration, MZn) or 2425 mg Zn/kg (high Zn concentration, HZn) mg Zn/kg feed for 1, 2 or 4 weeks. We observed that feeding the HZn diet for 1 week increased the level of activated T-helper cells (CD4+ and CD8αdim) compared with feeding MZn and LZn (P<0·05). In addition, we observed higher transcript amounts of interferon γ and T-box 21 (TBET) in the HZn group compared with the MZn and LZn groups (P<0·05). A gene set enrichment analysis revealed an over-representation of genes associated with ‘cytokine signalling in immune system’. Remarkably, feeding of a very high Zn dosage led to a switch in the immune response after 2 weeks. We detected higher relative cell counts of CD4+CD25high regulatory T-helper cells (P<0·05) and a higher expression of forkhead box P3 (FOXP3) transcripts (P<0·05). After 4 weeks of feeding a high-dosage Zn diet, the relative CD4+ T-cell count (P<0·05) and the relative CD8β+ T-cell count (P<0·1) were reduced compared with the MZn group. We hypothesise that after 1 week the cellular T-helper 1 response is switched on and after 2 weeks it is switched off, leading to decreased numbers of T-cells.

Objectives: The evaluation of public health interventions poses some challenges. As a consequence, health technology assessment (HTA) methods for public health interventions (PHI) have to be adapted. This study aimed to summarize the available guidance on methods for HTA of PHI.

Methods: We systematically searched for methodological guidance on HTA of PHIs. Our focus was on research synthesis methods to evaluate effectiveness. Relevant information was synthesized narratively in a standardized way.

Results: Only four guidance documents were identified specifically for HTAs of PHI. The approaches used for HTAs of PHIs are broader and more flexible than those for medical interventions. For this reason, there is a tendency to identify the intervention components and context factors that influence the effectiveness and transferability of an intervention rather than to assess its effectiveness in general. The details in the guidance vary without justification. Unjustified heterogeneity between the different guidance approaches is most pronounced for quality assessment, assessment of applicability, and methods to integrate qualitative and quantitative evidence. Descriptions for the assessment of integrity, heterogeneity, sustainability, context factors, and applicability are often vague.

Conclusions: The heterogeneity in approaches indicates that there is currently no consensus on methods to deal with the challenges of the PHI evaluations. A possible explanation for this may be that the methods are not sufficiently developed, and advantages and disadvantages of a certain method in relation to the research question (e.g., broad/focused) have not yet been sufficiently evaluated.

The physiological role of the gastrointestinal microbiota has become an important subject of nutrition research in pigs in the past years, and the importance of intestinal microbial activity in the etiology of disease is doubtless. This review summarizes the recent knowledge related to the microbial ecology of protein fermentation and the appearance of protein-derived metabolites along the pig intestine. The amount of fermentable protein depends on factors such as dietary protein concentration, protein digestibility due to secondary or tertiary structure, the interaction with dietary compounds or anti-nutritional factors, and the secretion of endogenous proteins into the gut lumen. High protein diets increase the luminal concentrations and epithelial exposure to putatively toxic metabolites and increase the risk for post-weaning diarrhea, but the mechanisms are not yet clarified. Although the use of fermentable carbohydrates to reduce harmful protein-derived metabolites in pigs is well-established, recent studies suggest that the inclusion of fermentable carbohydrates into diets with low protein digestibility or high dietary protein level may not ameliorate all negative effects with regard to epithelial response. Based on the current knowledge, the use of diets with low levels of high-quality protein may help to reduce the risk for intestinal disease in young pigs.

The present study investigated the influence of bacterial metabolites on monocarboxylate transporter 1 (MCT1) expression in pigs using in vivo, ex vivo and in vitro approaches. Piglets (n 24) were fed high-protein (26 %) or low-protein (18 %) diets with or without fermentable carbohydrates. Colonic digesta samples were analysed for a broad range of bacterial metabolites. The expression of MCT1, TNF-α, interferon γ (IFN-γ) and IL-8 was determined in colonic tissue. The expression of MCT1 was lower and of TNF-α and IL-8 was higher with high-protein diets (P< 0·05). MCT1 expression was positively correlated with l-lactate, whereas negatively correlated with NH3 and putrescine (P< 0·05). The expression of IL-8 and TNF-α was negatively correlated with l-lactate and positively correlated with NH3 and putrescine, whereas the expression of IFN-γ was positively correlated with histamine and 4-ethylphenol (P< 0·05). Subsequently, porcine colonic tissue and Caco-2 cells were incubated with Na-butyrate, NH4Cl or TNF-α as selected bacterial metabolites or mediators of inflammation. Colonic MCT1 expression was higher after incubation with Na-butyrate (P< 0·05) and lower after incubation with NH4Cl or TNF-α (P< 0·05). Incubation of Caco-2 cells with increasing concentrations of these metabolites confirmed the up-regulation of MCT1 expression by Na-butyrate (linear, P< 0·05) and down-regulation by TNF-α and NH4Cl (linear, P< 0·05). The high-protein diet decreased the expression of MCT1 in the colon of pigs, which appears to be linked to NH3- and TNF-α-mediated signalling.