Development and application of an interactive generic physiologically based pharmacokinetic (igPBPK) model for adult beef cattle and lactating dairy cows to estimate tissue distribution and edible tissue and milk withdrawal intervals for per- and polyfluoroalkyl substances (PFAS).

Humans can be exposed to per- and polyfluoroalkyl substances (PFAS) through dietary intake from milk and edible tissues from food animals. This study developed a physiologically based pharmacokinetic (PBPK) model to predict tissue and milk residues and estimate withdrawal intervals (WDIs) for multiple PFAS including PFOA, PFOS and PFHxS in beef cattle and lactating dairy cows. Results showed that model predictions were mostly within a two-fold factor of experimental data for plasma, tissues, and milk with an estimated coefficient of determination (R2) of >0.95. The predicted muscle WDIs for beef cattle were <1 day for PFOA, 449 days for PFOS, and 69 days for PFHxS, while the predicted milk WDIs in dairy cows were <1 day for PFOA, 1345 days for PFOS, and zero day for PFHxS following a high environmental exposure scenario (e.g., 49.3, 193, and 161 ng/kg/day for PFOA, PFOS, and PFHxS, respectively, for beef cattle for 2 years). The model was converted to a web-based interactive generic PBPK (igPBPK) platform to provide a user-friendly dashboard for predictions of tissue and milk WDIs for PFAS in cattle. This model serves as a foundation for extrapolation to other PFAS compounds to improve safety assessment of cattle-derived food products.

Burden of anemia and intestinal parasites in farmers and family members and owned livestock in two geographic locations in Senegal before and during the rainy seasons.

Different environmental conditions can impact the burden of anemia and intestinal parasite infections in human and livestock populations. The objective of this study was to compare the prevalence of anemia and intestinal parasite infections in farmers, family members, and owned sheep in two geographic locations along the Senegal River in June (end of the dry season) and September (rainy season). In Diawara, the prevalence of anemia in humans was high in June (74%) and remained high in September (75%) (p = 0.91). The prevalence of intestinal parasite infections increased from 7% in June to 54% in September (p < 0.05). Anemia was associated with age (children) and sex (women) (p < 0.05); but not with a positive diagnosis of intestinal parasite infection (p = 0.73). In sheep, the prevalence of anemia increased from 43% in June to 73% in September (p < 0.05), and the prevalence of intestinal parasite infections increased from 75% in June to 100% in September (p < 0.05). A positive diagnosis of Haemonchus contortus was associated with anemia (p = 0.05) and loss of body weight (2.4 kg) (p = 0.08). In Mpal, similar anemia and parasite infection trends were observed in children and sheep. The persistent high prevalence of anemia, and the impact of the rainy season on the burden of intestinal parasite infections in farmers, family members, and owned sheep can justify a One Health approach, where Senegal's ministries of health and of agriculture share resources for implementation and evaluation of government program efforts to reduce anemia in children and women, as well as morbidity and mortality in owned livestock; particularly in remote areas where public health services and veterinary services are very limited.

An Interactive Generic Physiologically Based Pharmacokinetic (igPBPK) Modeling Platform to Predict Drug Withdrawal Intervals in Cattle and Swine: A Case Study on Flunixin, Florfenicol, and Penicillin G.

Violative chemical residues in edible tissues from food-producing animals are of global public health concern. Great efforts have been made to develop physiologically based pharmacokinetic (PBPK) models for estimating withdrawal intervals (WDIs) for extralabel prescribed drugs in food animals. Existing models are insufficient to address the food safety concern as these models are either limited to 1 specific drug or difficult to be used by non-modelers. This study aimed to develop a user-friendly generic PBPK platform that can predict tissue residues and estimate WDIs for multiple drugs including flunixin, florfenicol, and penicillin G in cattle and swine. Mechanism-based in silico methods were used to predict tissue/plasma partition coefficients and the models were calibrated and evaluated with pharmacokinetic data from Food Animal Residue Avoidance Databank (FARAD). Results showed that model predictions were, in general, within a 2-fold factor of experimental data for all 3 drugs in both species. Following extralabel administration and respective U.S. FDA-approved tolerances, predicted WDIs for both cattle and swine were close to or slightly longer than FDA-approved label withdrawal times (eg, predicted 8, 28, and 7 days vs labeled 4, 28, and 4 days for flunixin, florfenicol, and penicillin G in cattle, respectively). The final model was converted to a web-based interactive generic PBPK platform. This PBPK platform serves as a user-friendly quantitative tool for real-time predictions of WDIs for flunixin, florfenicol, and penicillin G following FDA-approved label or extralabel use in both cattle and swine, and provides a basis for extrapolating to other drugs and species.

Anemia and intestinal parasites in farmers and family members and sheep in two agro-ecological zones in Senegal.

The burden of anemia in Senegal is high, particularly in children and women in rural households. The main objectives of the study reported here were (i) to measure and compare the prevalence of anemia and intestinal parasitic infections in farmers and family members and sheep in two agro-ecological zones in Senegal and (ii) to examine the association between anemia and age or sex in farmers and family members. The study was conducted in Mpal (250 km from Dakar, the capital city) and Diawara (700 km from Dakar, a remote location near the Malian border). In humans, the prevalence of anemia was higher in Diawara (64/86 = 74%), compared to Mpal (13/29 = 45%) (p < 0.01). Using logistic regression, the odds of anemia were 20.3, 5.7, and 3.2 times higher in children 1-4 years old, children 5-12 years-old, and teenagers 13-19 years old, respectively, compared to adults 20-60 years old, after controlling for study site and sex (p < 0.05). In Diawara, the odds of anemia were 2.9 times higher in women, compared to men, after controlling for age (p = 0.06). The prevalence of intestinal parasites (Giardia sp.) was the same (7%) at both locations. In sheep, the prevalence of low packed cell volume (PCV) and low body condition was higher in Diawara (48/60 = 60% and 11/60 = 18%, respectively), compared to Mpal (23/46 = 50% and 0/46 = 0%, respectively) (p < 0.05). Clinical anemia was associated (p < 0.01) with low PCV and a positive diagnosis of H. contortus. Overall, the prevalence of anemia was higher in farmers and family members and owned sheep in Diawara. In addition, anemia was more common in children and women, an indication that intra-household food allocation may be regulated in favor of men and older age groups. The consequences of livestock affected with anemia and undernutrition can be significant. High morbidity and mortality in livestock can lead to low household income, inadequate household access to and individual consumption of animal source foods, and subsequent risk of anemia in children and women in rural households in Senegal.

Development and Application of an Interactive Physiologically Based Pharmacokinetic (iPBPK) Model to Predict Oxytetracycline Tissue Distribution and Withdrawal Intervals in Market-Age Sheep and Goats.

Oxytetracycline (OTC) is a widely used antibiotic in food-producing animals. Extralabel use of OTC is common and may lead to violative residues in edible tissues. It is important to have a quantitative tool to predict scientifically based withdrawal intervals (WDIs) after extralabel use in food animals to ensure human food safety. This study focuses on developing a physiologically based pharmacokinetic (PBPK) model for OTC in sheep and goats. The model included 7 compartments: plasma, lung, liver, kidneys, muscle, fat, and rest of the body. The model was calibrated with serum and tissue (liver, muscle, kidney, and fat) concentration data following a single intramuscular (IM, 20 mg/kg) and/or intravenous (IV, 10 mg/kg) administration of a long-acting formulation in sheep and goats. The model was evaluated with independent datasets from Food Animal Residue Avoidance Databank (FARAD). Results showed that the model adequately simulated the calibration datasets with an overall estimated coefficient of determination (R2) of 0.95 and 0.92, respectively, for sheep and goat models and had acceptable accuracy for the evaluation datasets. Monte Carlo sampling technique was applied to predict the time needed for drug concentrations in edible tissues to fall below tolerances for the 99th percentiles of the population. The model was converted to a web-based interactive PBPK (iPBPK) interface to facilitate model applications. This iPBPK model provides a useful tool to estimate WDIs for OTC after extralabel use in small ruminants to ensure food safety and serves as a basis for extrapolation to other tetracycline drugs and other food animals.

Physiological parameter values for physiologically based pharmacokinetic models in food-producing animals. Part III: Sheep and goat.

This report is the third in a series of studies that aimed to compile physiological parameters related to develop physiologically based pharmacokinetic (PBPK) models for drugs and environmental chemicals in food-producing animals including swine and cattle (Part I), chickens and turkeys (Part II), and finally sheep and goats (the focus of this manuscript). Literature searches were conducted in multiple databases (PubMed, Google Scholar, ScienceDirect, and ProQuest), with data on relevant parameters including body weight, relative organ weight (% of body weight), cardiac output, relative organ blood flow (% of cardiac output), residual blood volume (% of organ weight), and hematocrit reviewed and statistically summarized. The mean and standard deviation of each parameter are presented in tables. Equations describing the growth curves of sheep and goats are presented in figures. When data are sufficient, parameter values are reported for different ages or production classes of sheep, including fetal sheep, lambs, and market-age sheep (mature sheep). These data provide a reference database for developing standardized PBPK models to predict drug withdrawal intervals in sheep and goats, and also provide a basis for extrapolating PBPK models from major species such as cattle to minor species such as sheep and goats.

Combined effect of mastitis and parity on pregnancy loss in lactating Holstein cows.

The main objective of this study was to examine the combined effect of mastitis and parity on pregnancy loss (PL) in lactating Holstein cows. A secondary objective was to estimate the cost of mastitis including that of PL attributable to mastitis. A total of 1,774 lactation periods from 1,047 Holstein cows with different parities from one dairy farm were included in a matched case-control study. All study cows were diagnosed pregnant by transrectal ultrasonography on day 33 after timed artificial insemination (TAI). Case cows (n = 222 lactations) were those later diagnosed non-pregnant by transrectal palpation on day 47 or 75 after TAI. Control cows (n = 1,552 lactations) were those confirmed pregnant by transrectal palpation on day 75 after TAI. Case cows were matched with eligible controls according to year of calving and calving-to-conception interval (CCI) ± 3 days. Cows with different parities were classified as exposed to subclinical mastitis (somatic cell score (SCS) > 4.5 in at least one Dairy Herd Improvement Association (DHIA) test day) or clinical mastitis (with or without evidence of subclinical mastitis) during two exposure periods: 1-42 days before breeding or 1-75 days during gestation (1 to PL diagnosis day in case cows, or 1-75 day in control cows). Conditional logistic regression was used to model the odds of PL as a function of previous exposure to mastitis in different parities. Cost of PL attributable to mastitis ($/case) among cows with mastitis was estimated based on attributable risk calculated in the epidemiologic analysis. We observed a higher than expected combined effect between exposure to mastitis (subclinical or clinical) before breeding and parity 3 or ≥ 4, and during gestation and parity ≥ 4 on PL. The cost of PL attributable to mastitis was highest ($196/case) in cows in parity ≥ 4 affected with clinical mastitis during gestation. Overall, study results indicate the impact of mastitis on PL is higher in older cows (parity ≥ 3). Dairy farmers and attending veterinarians can consider the combined effect of mastitis and parity when evaluating causes for PL and strategies for optimizing reproductive performance in dairy cows.

Mycoplasma bovis: Interactions with the Immune System and Failure to Generate an Effective Immune Response.

Host responses are often ineffective at clearing Mycoplasma bovis infection and may contribute to the pathogenesis of disease. M bovis possesses a surprisingly large repertoire of strategies to evade and modulate host responses. Unopsonized M bovis impairs phagocytosis and killing by neutrophils and macrophages. Apoptosis of neutrophils and lymphocytes is enhanced, whereas it is delayed in macrophages. Both proinflammatory and antiinflammatory cytokines are stimulated during M bovis infection depending on the cell type and location, and overall systemic responses tend to have a T-helper 2 bias. M bovis reduces proliferation of T cells and, in chronic infection, causes T-cell exhaustion.

Epidemiologic and economic analyses of pregnancy loss attributable to mastitis in primiparous Holstein cows.

The main objective of the study reported here was to examine the association between pregnancy loss (PL) and previous exposure to clinical or subclinical mastitis before breeding or during gestation in primiparous Holstein cows. A secondary objective was to estimate the cost of clinical mastitis during gestation, including that of PL attributable to mastitis in study cows. A total of 687 primiparous Holstein cows from 1 dairy farm were included in a matched case-control study. Study cows were declared pregnant via ultrasound on d 33 after timed artificial insemination (TAI). Case cows (n = 78) were those diagnosed as nonpregnant by rectal palpation on d 47 or 75 after TAI. Control cows were those confirmed as pregnant by rectal palpation on d 47 and 75 after TAI. Case cows were matched with eligible controls according to year of calving and calving-to-conception interval ±3 d. Cows were assigned to 1 of 3 groups: (1) cows not affected with clinical or subclinical mastitis; (2) cows affected with subclinical mastitis (Dairy Herd Improvement Association somatic cell score >4.5); and (3) cows affected with clinical mastitis during 2 exposure periods, 1 to 42 d before breeding or during gestation (1 to PL diagnosis day for case cows, and 1 to 75 d for control cows). Conditional logistic regression was used to model the odds of PL as a function of previous exposure to mastitis in study cows. Mastitis before breeding was not associated with PL. The odds of PL were 2.21 times greater in cows affected with clinical mastitis during gestation (95% confidence interval = 1.01, 4.83), compared with cows without mastitis, after controlling for breeding type and lameness. The cost of clinical mastitis during gestation was $149, which includes the cost ($27) of PL attributable to mastitis. In conclusion, this study provides evidence that clinical mastitis during gestation can cause PL in primiparous dairy cows leading to economic losses.

Evidence that mastitis can cause pregnancy loss in dairy cows: A systematic review of observational studies.

The objective of this study was to conduct a systematic review to identify and assess evidence and knowledge gaps in published observational studies that have investigated the relationship between mastitis and pregnancy loss (PL) in dairy cows. PubMed and ScienceDirect were used to search pertinent peer-reviewed research reports of interest. Screening of research reports was conducted at 3 levels: titles, abstracts, and full-text articles. The search identified 651 records for initial screening. The final screening process identified 8 qualified articles for review after removing 10 duplicate records, 582 titles, 31 abstracts, and 20 full-text articles. Two studies produced strong epidemiologic evidence indicating that (1) exposure to clinical mastitis during early gestation (first 45 d of gestation) is associated with subsequent PL during the following 90 d; and (2) subclinical mastitis 1 to 30 d before artificial insemination (AI) is associated with subsequent PL at 35 to 41 d of gestation. An additional study showed that exposure to clinical mastitis during early lactation in combination with low body condition can increase the risk of PL in dairy cows; however, the interaction effect between clinical mastitis and low body condition on PL was considered weak. Four other studies produced inconclusive evidence indicating that mastitis is a predisposing factor for PL in dairy cows, as the exposure risk period for mastitis overlapped with the follow-up period for diagnosis of PL in dairy cows. Finally, one study failed to identify a relationship between mastitis and PL in dairy cows. Further research is needed to (1) support the hypothesis that mastitis in combination with low body condition score (or other exposure factors) can increase the risk of PL, (2) compare the effect of clinical versus subclinical mastitis on PL, (3) compare the effect of mastitis before breeding and during gestation on PL, and (4) compare the effect of mastitis on PL in dairy cows during different lactations.

Evaluation of milk components as diagnostic indicators for rumen indigestion in dairy cows.

OBJECTIVE To identify milk component alterations that might be useful for detecting cows with rumen indigestion. DESIGN Prospective case-control study. ANIMALS 23 Holstein cows with rumen indigestion (cases) and 33 healthy cohorts (controls) from 1 herd. PROCEDURES Cases were defined as cows between 30 and 300 days postpartum with a > 10% decrease in milk yield for 2 consecutive milkings or > 20% decrease in milk yield from the 10-day rolling mean during any milking, abnormally decreased rumen motility, and no other abnormalities. Each case was matched with 2 healthy cows (controls) on the basis of pen, parity, days postpartum, and mean milk yield. Some cows were controls for multiple cases. All cows underwent a physical examination and collection of a rumen fluid sample for pH measurement at study enrollment. Individual-cow milk yield and milk component data were obtained for the 16 milkings before and after study enrollment. Rumen motility and pH and milk components were compared between cases and controls. RESULTS Rumen motility for cases was decreased from that of controls. Cases had an abrupt increase in milk fat percentage and the milk fat-to-lactose ratio during the 2 milkings immediately before diagnosis of rumen indigestion. Receiver operating characteristic analyses revealed that a 10% increase in the milk fat-to-lactose ratio had the highest combined sensitivity (57%) and specificity (85%) for identifying cows with rumen indigestion. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that a positive deviation in the milk fat-to-lactose ratio might be useful for identifying cows with rumen indigestion.

Field evaluation of a Mycoplasma bovis bacterin in young dairy calves.

Mycoplasma bovis is an important cause of pneumonia, otitis media and arthritis in young dairy calves, and there is a critical need for improved preventative strategies for this pathogen. We conducted a randomized, placebo-controlled, double-blinded field trial to determine the efficacy of a commercial M. bovis vaccine for the prevention of M. bovis-associated disease in calves. Calves (n=373) on 3 Florida dairies with a history of M. bovis infection received an M. bovis bacterin or a placebo, administered subcutaneously at 3, 14 and 35 days of age. One of the herds did not experience M. bovis-associated disease; for calves in the remaining 2 herds, the incidence risk for respiratory disease, otitis media and arthritis from 3 to 90 days of age was 0.64, 0.28 and 0.02, respectively. Vaccination had no effect on the age at first treatment for M. bovis-associated disease, incidence of respiratory disease, mortality, weight gain, or nasal colonization with M. bovis in the first 90 days of life. In one herd, vaccination was associated with an increased risk of otitis media. There was no association between M. bovis-specific serum antibody titers and morbidity in vaccinated calves. Under the field conditions in this study, this vaccine was not efficacious for the prevention of M. bovis-associated disease in young dairy calves.

Mycoplasma bovis Infections in young calves.

Mycoplasma bovis has emerged as an important pathogen of young intensively reared calves in North America. A variety of clinical diseases are associated with M bovis infections of calves, including respiratory disease, otitis media, arthritis, and some less common presentations. Clinical disease associated with M bovis often is chronic, debilitating, and poorly responsive to antimicrobial therapy. Current control measures are centered on reducing exposure to M bovis through contaminated milk or other sources, and nonspecific control measures to maximize respiratory defenses of the calf. This article focuses on the clinical and epidemiologic aspects of M bovis infections in young calves.

Hematogenous infection of Sprague-Dawley rats with Mycoplasma pulmonis: development of a model for maternal and fetal infection.

OBJECTIVES: The specific objective of this study was to conduct a dose response experiment with Mycoplasma pulmonis in Sprague-Dawley rats to develop a reproducible animal model of maternal and fetal infection that would provide a versatile mechanism to address the innate fetal immune response during intrauterine infection. STUDY DESIGN: Pregnant rats were infected intravenously at gestation day 14 with 0 (control), 10(1), 10(3), 10(5), and 10(7) colony forming units of M. pulmonis and necropsied at gestational day 18. Quantitative culture of maternal and fetal tissues as well as histopathologic examination of the placenta were performed. RESULTS: We have characterized a rat model of maternal and fetal infection that can be manipulated by alteration of infectious dose. Colonization of Sprague-Dawley rat dam and fetal tissues by M. pulmonis occurred in a dose-dependent manner after intravenous inoculation (P < .001). Placental lesion severity increased with infection dose (P = .0001). The minimum threshold dose required to establish infection of the dam and fetus was at least 10(3) colony forming units, with consistent colonization of maternal and fetal tissues achieved only with 10(7) colony forming units. In some instances, rat fetal tissues could be colonized in the absence of concomitant amniotic fluid colonization. Interestingly, there appeared to be a predilection for colonization of the reproductive tissues. CONCLUSIONS: In the Sprague-Dawley rat, the infection rate of both the dam and fetus can be controlled by the inoculum dose. Our data support the concept that hematogenous spread of M. pulmonis to the rat fetus can occur without amniotic fluid infection and suggest that the fetus itself can potentially seed the amniotic fluid with microorganisms. Importantly, manipulation of both the route of infection as well as infection dose provide a reproducible way to study both maternal and fetal immune response to infection during pregnancy.