The Impact of Cat Fostering on Older Adult Well-Being and Loneliness: A Feasibility Study.

OBJECTIVES: This feasibility study explored the impact of fostering a shelter cat on loneliness and well-being in older adults living alone without a pet. The study also examined the effect of cat fostering on older adults' interest in cat adoption when perceived barriers to adoption were removed. METHODS: A total of 29 adults (age ≥60) were paired with a cat and asked to foster for a minimum of 4 months (with an option to adopt). Participants completed surveys before placement with cats, with a follow-up at 1 and 4 months postplacement and 12 months if they adopted their cat. The survey included scales of loneliness, physical and mental health, self-efficacy, positive and negative affect, and comfort from a companion animal. Scores were compared across time using a Multivariable Linear Mixed Model. RESULTS: A total of 23 of 29 (79.3%) participants remained in the study for at least 4 months, and a majority (95.7%) adopted their cat. Differences in marginal means (adjusted for physical health) showed a significant improvement in loneliness from baseline to 4 months (p = .029). A similar 4-month improvement that approached statistical significance (adjusted p = .079) was observed for mental health. No other scales showed statistically significant changes across time. DISCUSSION: Fostering a shelter cat with the option for adoption may be an effective solution for alleviating loneliness and improving mental health in older adults. Interest in adopting foster cats was high when perceived barriers to adoption were removed.

Evaluation of red blood cell distribution width, neutrophil-to-lymphocyte ratio, and other hematologic parameters in canine acute pancreatitis.

OBJECTIVE: To determine if RBC distribution width (RDW), neutrophil-to-lymphocyte ratio (NLR), and other hematological parameters are associated with increased odds of in-hospital mortality, increased length of hospitalization (LOH), or disease severity as measured by the Canine Acute Pancreatitis Severity (CAPS) score in dogs with acute pancreatitis (AP). DESIGN: Retrospective, multicenter study from January 2016 to August 2020. SETTING: Four private emergency and specialty referral centers. ANIMALS: On initial case search, 118 client-owned dogs were identified with a clinical diagnosis of AP. Out of these cases, 114 dogs met inclusion criteria, defined as sudden onset of ≥2 compatible clinic signs (lethargy, anorexia, vomiting, or abdominal pain), a specific canine pancreatic lipase concentration >400 µg/L, hospital admission, as well as CBC and serum biochemistry run within 48 hours of initial hospitalization. Disease severity was calculated and measured using the CAPS score, in addition to LOH and in-hospital mortality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical endpoints were in-hospital mortality, LOH, and disease severity, as evaluated by the CAPS score. Overall in-hospital mortality was 36.8%. NLR was significantly associated with survival, with a higher percentage being associated with an increased likelihood of nonsurvival (odds ratio: 1.1, 95% confidence interval: 1.0-1.2; P = 0.006, adjusted P = 0.04). Increased NLR was found to be significantly associated with a longer LOH based on the unadjusted P-value (P = 0.02) but was not statistically significant based on a P-value adjusted for multiple comparisons (P = 0.12). No significant associations were noted when RDW, platelet-to-lymphocyte ratio, WBC count, mean platelet volume, RDW-to-platelet ratio, or RDW-to-total serum calcium ratio was evaluated against outcome measures. CONCLUSIONS: This study retrospectively evaluated the prognostic utility of several readily available hematological parameters in dogs hospitalized for AP. Dogs with an increased NLR may have a higher risk of in-hospital mortality and increased LOH, although future prospective studies are necessary to confirm these findings.

Prevalence, differences, and potential correlation to age, sex, breed, coat color, iris color, and geographic location in naturally occurring refractive errors in the normal equine eye from Germany and North Carolina.

PURPOSE: To evaluate the normal refractive state in horses in NCSU and ECMR and determine the prevalence of naturally occurring refractive errors and their association with breed, age, coat color, iris color, sex, and geographic location. METHODS: Horses from NCSU (January 2009-November 2012) and ECMR (January 2013-September 2016) underwent ophthalmic examination and streak retinoscopy. Location, color, breed, sex, and iris color were recorded. Gross and net refractive values for each meridian (horizontal and vertical), spherical refraction, astigmatism for both eyes, and anisometry were recorded, and statistical analyses were performed. RESULTS: There is excellent agreement in refraction between the eyes of the same horse (ICC = 0.89). The median net horizontal (H), vertical (V), and spherical refraction for the total population (n = 690) were H: +0.25 D (min. -6.50 D, max. +2.34 D), V: +0.25 D (min. -7.13 D, max. +2.75D), and spherical: +0.25 D (min. -6.82 D, max. +2.17 D), all with interquartile ranges of -0.25 to 0.25 D. Emmetropia (>-0.50 D and <+0.50 D; >-0.75 D and <+0.75 D) was present in 769/1380 eyes (55.7%) and 926/1380 eyes (67.1%), respectively. Anisometropia was present in 86/690 horses (12.5%). Sex, iris color, and location were significantly associated with refraction values, whereas age, breed, and coat color were not. CONCLUSIONS: Most eyes evaluated are emmetropic, or shifted myopically, with excellent agreement between eyes of the same horse. Sex, iris color, and geographic location appear to impact refraction in horses. SUPPORT: None.

Evaluation of a modified radiographic union scale for tibial fractures scoring system in staged bilateral tibial plateau leveling osteotomy procedures and comparison of first and second side radiographic bone healing.

OBJECTIVE: To evaluate the inter- and intra-rater reliability of the tibial plateau leveling osteotomy (TPLO) modified radiographic union scale for tibial fractures (mRUST), a semiquantitative scoring system, as compared with the subjective evaluation of radiographic union for staged TPLOs. STUDY DESIGN: Retrospective study. ANIMALS: Forty-eight dogs, 96 stifles. METHODS: Medical records were reviewed for dogs with bilateral cranial cruciate ligament injuries diagnosed at presentation that underwent staged bilateral TPLOs within 6 months and had both immediate and recheck postoperative radiographs. Radiographs were anonymized, reviewers were blinded, radiographic union was evaluated subjectively, and TPLO mRUST scores were assigned. RESULTS: The subjective evaluation's intra-rater reliability was 0.72 (Kappa 95% CI 0.65-0.79) and inter-rater reliability was 0.33 (Kappa 95% CI 0.28-0.39). The TPLO mRUST scoring system intra-rater reliability was 0.73 (95% CI 0.68-0.78) and inter-rater reliability was 0.56 (95% CI 0.41-0.68). There was no difference in the degree of bone healing quantified by the TPLO mRUST scoring system (95% CI - 0.1-1.2, P = .09) or subjective evaluation (P = .48) between the first and second side TPLOs. The TPLO mRUST scores were positively correlated with subjective healing (r = 0.94, 95% CI 0.92-0.96, P < .0001, and for scores ≥10/12, 99%, 244/246) were subjectively assigned as radiographically healed. CONCLUSION: The TPLO mRUST scoring system improved inter-rater reliability compared to subjective evaluation of radiographic union. CLINICAL SIGNIFICANCE: The TPLO mRUST scoring system should be considered as a semiquantitative supplemental tool for evaluating radiographic union.

Fracture rate and time to fracture in dogs with appendicular osteosarcoma receiving finely fractionated compared to coarsely fractionated radiation therapy: A single institution study.

BACKGROUND: Radiation therapy (RT) is used for local pain alleviation in dogs with appendicular osteosarcoma (OS), especially among dogs that are poor surgical candidates for amputation. However, many historical reports of fractionated protocols lack time to fracture and fracture rates. OBJECTIVES: The primary objectives of this retrospective study were to determine fracture rate and time to fracture of dogs receiving RT (coarse or fine fractionated) for appendicular OS. Secondary objectives were to evaluate tolerability and disease outcome measures. METHODS: Fifty-one dogs that received RT as part of treatment for appendicular OS were available for evaluation. Forty-five received coarse fractionation (C-RT, 8 or 6 Gy per fraction protocols [C-RT8 or C-RT6]) while the remaining six received fine fractionation (F-RT). RESULTS: The overall pathologic fracture rate was 37%. Pathologic fracture rate was significantly higher for dogs that received F-RT (5/6, 83%) compared to dogs that received C-RT (12/40, 30%, p = 0.021). In the 17 dogs that fractured, the overall median time to fracture was 57 days. For all dogs, the median progression free interval (PFI) and median overall survival time (OST) were 90 and 140 days, respectively. In a very small cohort of dogs (n = 7) treated with zoledronate and RT, fracture rate was 0% and extended survival times were noted. CONCLUSIONS: In conclusion, C-RT is recommended over F-RT due to lower risk of pathologic fracture and similar PFI. Prospective evaluation of combined C-RT and zoledronate, especially for dogs with poor surgical candidacy, is warranted for the treatment of canine appendicular osteosarcoma.

Single instead of triplicate intraocular pressure measurements in dogs do not substantially lower accuracy and precision but do slightly reduce statistical power.

OBJECTIVE: To compare single and triplicate applanation tonometry values across previous intraocular pressure (IOP) studies in dogs. ANIMALS: 116 ophthalmologically normal dogs. PROCEDURES: Triplicate IOP readings (n = 1432) from studies evaluating effect of anesthetic protocols were analyzed to estimate a range of probable differences between averaged triplicate and first, averaged and lowest, and first and lowest IOPs. The decrease in variability with triplicate measurements and the magnitude of effects on statistical power were quantified. RESULTS: The 2.5th to 97.5th interpercentile range for differences of averaged triplicate values minus first IOP readings was -3 to 2.7 mm Hg; for averaged minus lowest: 0 to 3.7 mm Hg; for first minus lowest: 0 to 5 mm Hg. The 95% prediction interval for differences in study group means (n = 160 groups, n = 5 to 11 eyes per group) based on averaged minus first measurements was -1.0 to 0.9 mm Hg with associated SDs reduced by 4% on average. Analysis of previous studies using averaged instead of first IOP values resulted in minimal decreases in SEs of 3-9% (0.03 to 0.09 mm Hg). Of 11 comparisons found significant with averaged data, 2 (18%) were found nonsignificant with first measurements. Of 96 comparisons found nonsignificant with averaged data, 3 (3%) were found significant with first measurements. CLINICAL RELEVANCE: With applanation tonometry in ophthalmologically normal dogs, no clinically meaningful difference was found between the first, lowest, or averaged triplicate IOP measurements, but the first reading has a larger variance and hence will result in lower statistical power.

Clinical findings associated with blunt ocular trauma in horses: a retrospective analysis.

OBJECTIVE: Identify ocular findings associated with blunt ocular trauma to aid in differentiation from other equine ocular diseases. STUDY DESIGN: Retrospective case-control study. METHODS: Medical records of horses at the Equine Clinic Munich-Riem, Munich, Germany and Auburn University, College of Veterinary Medicine were reviewed. Age, sex, breed, laterality, and clinical findings on ophthalmic examination, as well as an observed (confirmed) or unobserved (suspected) history of trauma, were recorded. Statistical analysis was performed to identify any correlation between clinical signs and blunt ocular trauma. Fifty-nine clinical signs were evaluated, and their association with blunt ocular trauma and non-traumatic uveitis was determined. The frequency of clinical signs associated with non-traumatic uveitis was also reported. RESULTS: Fifty-five eyes affected with blunt trauma were included. The comparison group consisted of 233 eyes (168 horses) diagnosed with non-traumatic uveitis. The most frequent ocular findings after BOT included cataract (36/55, 65.5%), corneal edema (26/55, 47.2%), decreased intraocular pressure (23/55, 41.8%), aqueous flare (19/55, 34.5%), lens subluxation, luxation, or lens loss (18/55, 32.7%), fibrin in the anterior chamber (18/55, 32.7%), hyphema (16/55, 29.1%), peripapillary depigmentation ("butterfly lesion") (16/55, 29.1%), conjunctival hyperemia (16/55, 29.1%), corneal fibrosis (15/55, 27.3%), corpora nigra avulsion (14/55, 25.5%), blepharospasm (13/55, 23.6%), and iridodialysis (11/55, 20.0%). CONCLUSIONS: The characteristic pattern of ocular signs associated with blunt ocular trauma may assist in differentiation from other types of uveitis and may improve interpretation of ocular lesions identified during pre-purchase examinations. This study also represents the first peer-reviewed documented and photographed cases of iridodialysis in the horse.

Use of autologous serum or Vizoovet to improve healing rates of spontaneous chronic corneal epithelial defects after diamond burr debridement in dogs.

PURPOSE: To determine whether the use of autologous serum or Vizoovet® improved healing rates of spontaneous chronic corneal epithelial defects (SCCEDs) after diamond burr debridement (DBD) in dogs. STUDY DESIGN: Two parallel group randomized prospective study with a historical control group. MATERIALS AND METHODS: Canine patients having undergone DBD for treatment of SCCEDs were included. Data for the control group (ofloxacin only) were gathered from patient records. Patients were randomly assigned to treatment groups for post-procedural medical treatments of ofloxacin and autologous serum (group 1) or ofloxacin and Vizoovet®, an all-natural eyed drop containing propolis, aloe vera, and chamomile (group 2). Each dog was examined between 2 and 3 weeks until the cornea was fluorescein stain negative. Data points collected included age, sex, breed, type of medications used, retention of bandage contact lens (BCL), time to healing, and number of DBD performed. RESULTS: A total of 120 dogs, each contributing one eye to the study, underwent DBD for SCCEDs. Mean (± standard deviation) days until healed were 20.1 ± 11.1 days, 16.3 ± 4.5 days, and 16.0 ± 3.7 days for the control group, group 1, and group 2, respectively. There was a marginally significant difference in days until healed between groups (p = .0515). SCCEDs healed significantly faster in group 2 (p = .03) and marginally faster in group 1 (p = .06) compared with the control group. Days until healing between group 1 and 2 were not significantly different (p = .76). CONCLUSIONS: As compared to the control group, use of Vizoovet® as adjunctive medical treatment resulted in shorter corneal healing time after DBD.

Effect of topical non-steroidal anti-inflammatory drugs on healing times and complications in dogs with spontaneous chronic corneal epithelial defects.

BACKGROUND: Little is published regarding topical NSAID effect on corneal healing in dogs. This retrospective cohort study aimed to compare healing times and complications in dogs with spontaneous chronic corneal epithelial defects (SCCED) treated with and without topical non-steroidal anti-inflammatory drugs (NSAID). METHODS: Medical records of 66 dogs (71 eyes) diagnosed with SCCED between 2008 and 2019 were included. Eyes were divided into: (1) those receiving topical NSAIDs (n = 33) versus (2) those not receiving topical NSAID (n = 38). Follow-up until healed, such as comfortable eye, negative fluorescein stain was required. Use of topical or systemic anti-inflammatories outside of NSAID or presence of ocular disorders or systemic endocrinopathies that may contribute to delayed healing resulted in study exclusion. RESULTS: Healing times were significantly longer in eyes that received topical NSAID (p = 0.008), however, the use of more topical medications for treatment was also associated with longer healing times (p = 0.001). The majority of eyes in the NSAID group received multiple medications, compared to the non-NSAID group, so it was not possible to separate the effects of NSAID from a number of medications. Complications occurred in three eyes of three dogs within the NSAID group. CONCLUSIONS: In these canine SCCED eyes, the use of more topical medications, including NSAID, was associated with significantly delayed healing time.

Description of and complications associated with reinforced, free-form external skeletal fixation for treatment of appendicular fractures in cats: 46 cases (2010-2019).

OBJECTIVE: To describe a modified technique for reinforced, free-form external skeletal fixation (rFF-ESF) of appendicular fractures in cats and identify factors associated with development of complications. ANIMALS: 46 cats with fractures repaired with rFF-ESF at Angell Animal Medical Center between 2010 and 2019. PROCEDURES: Medical records were reviewed for information on signalment, affected bone, fracture location and orientation, degree of comminution, severity (open vs closed), fixator type, number of fixation pins, use of an intramedullary pin (yes vs no), surgeon experience (staff surgeon vs surgical resident), anesthesia time, surgery time, perioperative antimicrobial administration, concurrent surgical procedures, intraoperative complications, postoperative alignment, whether fixator destabilization was performed, and time to complete fixator removal. Postoperative complications were recorded. RESULTS: 43 of the 46 (93%) cats had a successful outcome, with a median time to complete fixator removal of 8 weeks (range, 3 to 61 weeks). Twelve of the 46 (26%) cats had major (n = 3) or minor (9) complications. In univariable analyses, 4 factors were significantly associated with development of postoperative complications: body weight (OR for each 1-kg increase in weight, 1.8), tibial fracture (vs fracture of any other long bone; OR, 16), use of a type 2 fixator (vs a type 1 fixator; OR, 11), and use of destabilization (vs no destabilization; 7). CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that rFF-ESF can be successfully used to stabilize a variety of appendicular fractures in cats. Further studies are required to compare rFF-ESF with other fracture fixation methods.

Effects of 0.02% netarsudil ophthalmic solution on intraocular pressure of normotensive dogs.

OBJECTIVES: To evaluate the effect of QD or BID 0.02% netarsudil ophthalmic solution (Aerie Pharmaceuticals) on intraocular pressure (IOP) in normotensive dogs and to describe any adverse effects. ANIMALS STUDIED: Normotensive Labrador retriever dogs were included in this study: 10 received netarsudil in one eye and artificial tears in the contralateral eye QD, and 10 received netarsudil in one eye and artificial tears in the contralateral eye BID. PROCEDURES: Intraocular pressure curves were acquired over a 3-day acclimation period, 5-day dosing period (QD or BID-10 dogs/group), and 3-day recovery period. Toxicity was assessed daily using slit-lamp biomicroscopy and the semiquantitative preclinical ocular toxicology scoring system. RESULTS: Once-daily dosing did not lower IOP over the entire 5-day dosing period (95% CI 0.1 to -0.9 mm Hg, P = .20) or on the last day of dosing (95% CI 0.4 to -0.9 mm Hg, P = .65). Twice-daily dosing resulted in a statistically significant, but clinically unimportant, IOP reduction over the entire 5-day dosing period (-0.6 mm Hg; 95% CI 0.05 to -1.1 mm Hg, P = .02) and on the last day of dosing (-0.9 mm Hg; 95% CI 0.2 to -1.5 mm Hg, P = .003). Adverse events were limited to transient mild-to-moderate conjunctival hyperemia during the dosing phase in eyes receiving netarsudil vs control (P < .0001). CONCLUSIONS: Netarsudil 0.02% ophthalmic solution twice daily resulted in a small, statistically significant, but clinically unimportant, IOP reduction in normotensive dogs. Future studies should investigate efficacy in glaucomatous dogs.

Clinical assessment of heartworm-infected Beagles treated with a combination of imidacloprid/moxidectin and doxycycline, or untreated.

BACKGROUND: Administration of moxidectin topically and doxycycline PO has been utilized experimentally as an alternative treatment for heartworm disease. However, clinical effects of this protocol remain poorly characterized. OBJECTIVE: To evaluate the clinical and postmortem findings associated with administration of doxycycline and monthly 10% imidacloprid + 2.5% moxidectin (IMD + MOX, Advantage Multi/Advocate) to Dirofilaria immitis-experimentally infected as compared to nontreated control dogs. ANIMALS: Sixteen purpose-bred, female, Beagle dogs. METHODS: Prospective, blinded, experimental study. Animals with surgically transplanted adult heartworms were randomized into 2 study groups of equal size: a nontreated control group (n = 8) and an IMD + MOX and doxycycline-treated group (n = 8). Randomization was performed using a complete block design according to circulating microfilarial concentrations, measured before treatment. Serum biochemical profiles, CBCs, thoracic radiographs and echocardiograms were performed prior to and 3 weeks after transplantation, and monthly for 10 months. Postmortem gross and histopathologic evaluations were performed. RESULTS: Compared to control animals, mean ± SD serum alanine aminotransferase (181 ± 203 U/L vs 33 ± 7 U/L; P < .0001) and alkaline phosphatase (246 ± 258 U/L vs 58 ± 19 U/L; P < .0001) activities were significantly higher in the treated group on day 28. Radiographic and echocardiographic evidence of heartworm disease was observed in both groups; however, no significant differences in these variables were noted between groups. Mean ± SD pulmonary arterial thrombus score was significantly higher in the treated vs nontreated group (3.9 ± 0.4 and 1.5 ± 2.1, respectively; P = .01). CONCLUSIONS AND CLINICAL IMPORTANCE: The treatment protocol was well-tolerated with no clinically relevant adverse effects for any variable evaluated during the observational period.

Adenovirus 36, adiposity, and bone strength in late-adolescent females.

Adenovirus 36 (Ad36) is the only adenovirus to date that has been linked with obesity in humans. Our previous studies in late-adolescent females suggest that excess weight in the form of fat mass is associated with lower cortical bone strength. The purpose of this study was to assess the relationship between Ad36-specific antibodies, adiposity, and bone strength in our sample of late-adolescent females. A cross-sectional study of 115 females aged 18 to 19 years was performed. Participants were classified according to adiposity by dual-energy X-ray absorptiometry (body fat percentage as normal-fat [ < 32% body fat; n = 93] or high-fat [ ≥ 32% body fat; n = 22]), and according to the presence of Ad36-specific neutralizing antibodies. Peripheral quantitative computed tomography measured bone parameters at the 4% (trabecular bone) and 20% (cortical bone) site, and muscle cross-sectional area (MCSA) at the 66% site, from the distal metaphyses of the radius and the tibia. Bone strength was determined from volumetric bone mineral density and bone geometry to calculate bone strength index (BSI; trabecular site) and polar strength-strain index (SSI; cortical site). After adjustment for MCSA and limb length, radial SSI was lower in Ad36+ versus Ad36- subjects from the high-fat group (p < 0.03), but not the normal-fat group. No significant differences were observed between groups in tibial SSI or BSI. These data support an association of adiposity and cortical bone strength at the radius with the presence of neutralizing antibodies to Ad36 in late-adolescent females.

Evaluation of methylprednisolone and triamcinolone for the induction and maintenance treatment of pruritus in allergic cats: a double-blinded, randomized, prospective study.

BACKGROUND: Oral triamcinolone (T) and methylprednisolone (M) have been recommended at various dosages for the control of pruritus associated with feline allergic dermatitis. OBJECTIVES: The first objective was to determine effective dosages of methylprednisolone (Pfizer, New York, NY, USA) and triamcinolone (Boehringer Ingelheim Vetmedica, Inc., St Joseph, MO, USA) required to induce remission from pruritus associated with feline allergic dermatitis. The second objective was to compare efficacy of several different alternate day maintenance dosages. The third objective was to determine whether laboratory abnormalities occurred at effective dosages. ANIMALS: Thirty-two client-owned allergic cats were randomly assigned to the M or T groups. METHODS: Owners reported weekly on pruritus score and behavioural changes. Remission was defined as a pruritus score of ≤2/10, with 0 as the least and 10 as the most pruritic. Serum chemistry, complete blood count, fructosamine and urinalysis were assessed on day 0, at the end of the 7-14 day induction phase and at study completion. RESULTS: Mean once daily doses required for induction were 1.41 mg/kg for M and 0.18 mg/kg for T. Mean alternate day maintenance doses were 0.54 mg/kg for M and 0.08 mg/kg for T. There was a statistically significant decrease in eosinophils and increase in fructosamine for both groups from baseline to study completion. Fructosamine levels did not exceed the reference range in any case. CONCLUSIONS: These results suggest that triamcinolone is approximately seven times as potent as methylprednisolone, and that these dosages are efficacious and well tolerated for the control of pruritus in allergic cats.

Quantitative evaluation of dichloroacetic acid kinetics in human--a physiologically based pharmacokinetic modeling investigation.

Dichloroacetic acid is a common disinfection by-product in surface waters and is a probable minor metabolite of trichloroethylene. Dichloroacetic acid (DCA) liver carcinogenicity has been demonstrated in rodents but epidemiological evidence in humans is not available. High doses of DCA ( approximately 50mg/kg) are used clinically to treat metabolic acidosis. Biotransformation of DCA by glutathione transferase zeta (GSTzeta) in the liver is the major elimination pathway in humans. GSTzeta is also inactivated by DCA, leading to slower systemic clearance and nonlinear pharmacokinetics after multiple doses. A physiologically based pharmacokinetic (PBPK) model was developed to quantitatively describe DCA biotransformation and kinetics in humans administered DCA by intravenous infusion and oral ingestion. GSTzeta metabolism was described using a Michaelis-Menten equation coupled with rate constants to account for normal GSTzeta synthesis, degradation and irreversible covalent binding and inhibition by the glutathione-bound-DCA intermediate. With some departures between observation and model prediction, the human DCA PBPK model adequately predicted the DCA plasma kinetics over a 20,000-fold range in administered doses. Apparent inhibition of GSTzeta mediated metabolism of DCA was minimal for low doses of DCA (microg/kg day), but was significant for therapeutic doses of DCA. Plasma protein binding of DCA was assumed to be an important factor influencing the kinetics of low doses of DCA (microg/kg day). Polymorphisms of GSTzeta may help explain inter-individual variability in DCA plasma kinetics and warrants evaluation. In conclusion, using a previously published rodent DCA PBPK model (Keys, D.A., Schultz, I.R., Mahle, D.A., Fisher, J.W., 2004. A quantitative description of suicide inhibition of dichloroacetic acid in rats and mice. Toxicol. Sci. 82, 381-393) and this human DCA PBPK model, human equivalent doses (HEDs) were calculated for a 10% increase in mice hepatic liver cancer (2.1mg/kg day). The HEDs for the dosimetrics, area-under-the-concentration-curve (AUC) for total and free DCA in plasma, AUC of DCA in liver and amount of DCA metabolized per day were 0.02, 0.1, 0.1 and 1.0mg/kg day, respectively. Research on the mechanism of action of DCA and the relevance of mouse liver cancer is needed to better understand which dosimetric may be appropriate for extrapolation from animal studies to human.

Low-dose effects of ammonium perchlorate on the hypothalamic-pituitary-thyroid axis of adult male rats pretreated with PCB126.

The objective of this research was to characterize the disturbances in the hypothalamic-pituitary-thyroid (HPT) axis resulting from exposure to a binary mixture, 3,3',4,4',5-pentachlorobiphenyl (PCB126) and perchlorate (ClO(4)(-)), known to cause hypothyroidism by different modes of action. Two studies were conducted to determine the HPT axis effects of ClO(4)(-) on adult male Sprague-Dawley rats pretreated with PCB126. In dosing study I, rats were administered a single oral dose of PCB126 (0, 7.5, or 75 microg/kg) on day 0 and 9 days later ClO(4)(-) (0, 0.01, 0.1, or 1 mg/kg day) was added to the drinking water until euthanasia on day 22. Significant dose-dependent trends were found for all thyroid function indices measured following ClO(4)(-) in drinking water for 14 days. Seventy-five micrograms PCB126/kg resulted in a significant increase in hepatic T(4)-glucuronide formation, causing a decline in serum thyroxine and fT(4), and resulting in increased serum thyroid-stimulating hormone (TSH). Serum TSH was also increased in animals that received 7.5 microg PCB126/kg; no other HPT axis alterations were found in these animals. When pretreated with PCB126, the ClO(4)(-) dose trends disappeared, suggesting a less than additive effect on the HPT axis. In dosing study II, animals were given lower doses of PCB126 (0, 0.075, 0.75, or 7.5 microg/kg) on day 0, and followed with ClO(4)(-) (0 or 0.01 mg/kg day) in drinking water beginning on day 1 and continuing for several days to explore transient HPT axis effects. No statistical effects were seen for PCB126 or ClO(4)(-) alone, and no perturbations were found when administered sequentially in dosing study II. In conclusion, these studies demonstrate that HPT axis disturbances following exposure to ClO(4)(-) are less than additive when pretreated with relatively high doses of PCB126. At relatively low doses, at or near the no-observed-effect-level for PCB126 and ClO(4)(-), no interactions between the chemicals occur.

A quantitative description of suicide inhibition of dichloroacetic acid in rats and mice.

Dichloroacetic acid (DCA), a minor metabolite of trichloroethylene (TCE) and water disinfection byproduct, remains an important risk assessment issue because of its carcinogenic potency. DCA has been shown to inhibit its own metabolism by irreversibly inactivating glutathione transferase zeta (GSTzeta). To better predict internal dosimetry of DCA, a physiologically based pharmacokinetic (PBPK) model of DCA was developed. Suicide inhibition was described dynamically by varying the rate of maximal GSTzeta-mediated metabolism of DCA (Vmax) over time. Resynthesis (zero-order) and degradation (first-order) of metabolic activity were described. Published iv pharmacokinetic studies in naive rats were used to estimate an initial Vmax value, with Km set to an in vitro determined value. Degradation and resynthesis rates were set to estimated values from a published immunoreactive GSTzeta protein time course. The first-order inhibition rate, kd, was estimated to this same time course. A secondary, linear non-GSTzeta-mediated metabolic pathway is proposed to fit DCA time courses following treatment with DCA in drinking water. The PBPK model predictions were validated by comparing predicted DCA concentrations to measured concentrations in published studies of rats pretreated with DCA following iv exposure to 0.05 to 20 mg/kg DCA. The same model structure was parameterized to simulate DCA time courses following iv exposure in naive and pretreated mice. Blood and liver concentrations during and postexposure to DCA in drinking water were predicted. Comparisons of PBPK model predicted to measured values were favorable, lending support for the further development of this model for application to DCA or TCE human health risk assessment.

The Acute Exposure Guideline Level (AEGL) program: applications of physiologically based pharmacokinetic modeling.

The primary aim of the Acute Exposure Guideline Level (AEGL) program is to develop scientifically credible limits for once-in-a-lifetime or rare acute inhalation exposures to high-priority, hazardous chemicals. The program was developed because of the need of communities for information on hazardous chemicals to assist in emergency planning, notification, and response, as well as the training of emergency response personnel. AEGLs are applicable to the general population, including children, the elderly, and other potentially susceptible subpopulations. AEGLs are the airborne concentrations of chemicals above which a person could experience notable discomfort or irritation (AEGL-1); serious, long-lasting health effects (AEGL-2); and life-threatening effects or death (AEGL-3). AEGLs are determined for five exposure periods (10 and 30 min and 1, 4, and 8 h). Physiologically based pharmacokinetic (PBPK) models can be very useful in the interspecies and time scaling often required here. PBPK models are used for the current article to predict AEGLs for trichlorethylene (TCE), based on the time course of TCE in the blood and/or brain of rats and humans. These AEGLs are compared to values obtained by standard time-scaling methods. Comprehensive toxicity assessment documents for each chemical under consideration are prepared by the National Advisory Committee for AEGLs, a panel comprised of representatives of federal, state, and local governmental agencies, as well as industry and private-sector organizations. The documents are developed according to National Research Council (NRC) guidelines and must be reviewed by the NRC Subcommittee on Acute Exposure Guideline Levels before becoming final. AEGLs for 18 chemicals have been published, and it is anticipated that 40 to 50 chemicals will be evaluated annually.

Tissue dosimetry expansion and cross-validation of rat and mouse physiologically based pharmacokinetic models for trichloroethylene.

Trichloroethylene (TCE), a volatile liquid used as a degreasing agent, is a common environmental pollutant. In 2001, the EPA published a draft risk assessment for TCE that incorporates dosimetry predictions of physiologically based pharmacokinetic (PBPK) models. The current modeling effort represents an expansion and extensive tissue dosimetry validation of rodent PBPK models for TCE. The pharmacokinetics of TCE in male Sprague-Dawley (S-D) rats were characterized (1) during and after inhalation exposure to 50 or 500 ppm TCE, (2) following administration of 8 mg/kg TCE PO, and (3) following intra-arterial injection of 8 mg/kg TCE. Blood and tissues (including liver, kidney, fat, skeletal muscle, heart, spleen, gastrointestinal tract, and brain) were collected at selected time-points from 5 min up to 24 h post initial exposure. The fat compartment was modified to be diffusion-limited to predict the observed slow release of TCE from the fat. The addition of a deep liver compartment was necessary to accurately predict the slower hepatic clearance of TCE for all three exposure routes. Simulations of liver concentrations following gavage of male B6C3F1 mice with 300-2000 mg/kg TCE were also improved with the addition of a deep liver compartment. Liver predictions were calibrated and validated using a cross-validation technique novel to PBPK modeling. Splitting of compartments did not significantly affect predictions of TCE concentrations in the liver, fat, or venous blood. This model expansion and validation increases both the utility and our confidence in the current use of rodent TCE PBPK models in human health risk assessment.

Accumulation of perchlorate in tobacco plants: development of a plant kinetic model.

Previous studies have shown that tobacco plants are tolerant of perchlorate and will accumulate perchlorate in plant tissues. This research determined the uptake, translocation, and accumulation of perchlorate in tobacco plants. Three hydroponics growth studies were completed under greenhouse conditions. Depletion of perchlorate in the hydroponics nutrient solution and accumulation of perchlorate in plant tissues were determined at two-day intervals using ion chromatography. Perchlorate primarily accumulated in tobacco leaves, yielding a substantial storage capacity for perchlorate. Mass balance results show that perchlorate degradation was negligible in plants. Tobacco plants were shown to effectively accumulate perchlorate over a wide range of initial concentrations (10 ppb to 100 ppm) from the hydroponics solution. Results suggest that plants are potential plants for the phytoremediation of perchlorate. A mathematical model was developed to describe the distribution of perchlorate in tobacco plants under rapid growth conditions. The Plant Kinetic (PK) model defined a plant as a set of compartments, described by mass balance differential equations and plant-specific physiological parameters. Data obtained from a separate hydroponics growth study with multiple solution perchlorate concentrations were used to validate predicted root, stem, and leaf concentrations. There was good agreement between model predictions and measured concentrations in the plant. The model, once adequately validated, can be applied to other terrestrial plants and inorganic chemicals currently used for both phytoremediation and ecological risk assessment.