Citizen science chlorine surveillance during the Flint, Michigan federal water emergency.

Rising incidence of waterborne diseases including Legionellosis linked to low chlorine residuals in buildings and the availability of inexpensive testing options, create an opportunity for citizen science chorine monitoring to complement sampling done by water utilities. University researchers and Flint residents coordinated a citizen science chlorine surveillance campaign in Flint, Michigan in 2015-19, that helped expose the nature of two deadly Legionnaires Disease outbreaks in 2014-2015 during the Flint Water Crisis and progress of system recovery during the Federal emergency. Results obtained with an inexpensive color wheel were in agreement with a digital colorimeter (R2 =0.99; p = 2.81 × 10-21) at 15 sites geographically distributed across Flint. Blinded tests revealed good agreement between official (n = 2051) and citizen (n = 654) data in terms of determining whether regulatory guidelines for chlorine were met, but a discovery that the citizen data were statistically lower than the city's (p<0.00001) especially in warm summer months led to recommendations for increased flushing of service lines before measurements. This work suggests that expanded citizen surveillance of chlorine, site specific flushing advice, and guidance on decisions about water heater set point could help consumers reduce Legionella risks in their homes. Citizen science initiatives for chlorine monitoring offer a unique opportunity for mutually beneficial collaborations between consumers and utilities to reduce the main source of waterborne disease in developed countries.

The development of bioresorbable composite polymeric implants with high mechanical strength.

Implants for the treatment of tissue defects should mimic the mechanical properties of the native tissue of interest and should be resorbable as well as biocompatible. In this work, we developed a scaffold from variants of poly(glycolic) acid which were braided and coated with an elastomer of poly(glycolide-co-caprolactone) and crosslinked. The coating of the scaffold with the elastomer led to higher mechanical strength in terms of compression, expansion and elasticity compared to braids without the elastomer coating. These composite scaffolds were found to have expansion properties similar to metallic stents, utilizing materials which are typically much weaker than metal. We optimized the mechanical properties of the implant by tuning the elastomer branching structure, crosslink density, and molecular weight. The scaffolds were shown to be highly resorbable following implantation in a porcine femoral artery. Biocompatibility was studied in vivo in an ovine model by implanting the scaffolds into femoral arteries. The scaffolds were able to support an expanded open lumen over 12 months in vivo and also fully resorbed by 18 months in the ovine model.

Immunotoxicity evaluation of nelfinavir in rats.

The objective of these investigations was to determine whether exposure to the HIV-1 protease inhibitor nelfinavir compromises immune function in Sprague Dawley rats. Animals (20/sex per group) were exposed orally for 1 or 6 months to nelfinavir at doses of 0 (1% carboxymethylcellulose vehicle), 100, 300 or 1000 mg/kg per day. Animals were observed daily for morbidity/mortality and for clinical signs of toxicity. Body weights were recorded weekly (weeks 1-14) and then monthly thereafter and at study termination. At termination (1 month or 6 months; 10/sex per group), serum was collected and retained for toxicokinetic analysis. The spleen, thymus and liver were removed from each animal and weighed; thymuses and liver were discarded after weighing. Spleens were prepared and immunophenotyping, natural killer (NK) cell activity, and proliferative responses to mitogenic stimuli (e.g., concanavalin A, Salmonella typhimurium) were evaluated. There were no treatment-related effects on immune cell populations (absolute or percent values) or in proliferative responses. At the 1-month interval, a decrease in NK cell activity (0.45-fold control) was noted in male rats at 100 and 1000 mg/kg per day but not at the middle dose of 300 mg/kg per day. Female rats at 1 month were noted for an increase in NK cell activity (1.4-fold control) at 100 mg/kg per day, but there was no difference in the NK response between vehicle-treated animals and those exposed to higher doses of nelfinavir. No effects on NK activity were noted in female animals after 6 months of nelfinavir treatment. Assay difficulties prevented evaluation of male rats at the 6-month interval. Taken together, the absence of a dose-response effect for NK activity in male rats treated for 1 month, the lack of suppressive effects in females treated for either 1 or 6 months, and the unchanged splenic NK cell numbers in nelfinavir-treated animals at both 1 and 6 months suggest that the decreased NK activity noted in male rats at 1 month is not biologically relevant. It was therefore concluded that, under the experimental conditions used, oral treatment with nelfinavir for 1 or 6 months at doses up to 1000 mg/ kg per day is not immunosuppressive in rats. C8hr values following nelfinavir treatment at 1000 mg/kg per day for 6 months were between 1- and 2.7-fold the reported Cmax values in humans.

Lack of respiratory and contact sensitizing potential of the intranasal antiviral drug candidate rupintrivir (AG7088): a weight-of-the-evidence evaluation.

Rupintrivir, also known as AG7088, is a small molecule 3C protease inhibitor designed to target human rhinovirus as a potential intranasal treatment for the common cold. The ability of rupintrivir to induce both respiratory and contact hypersensitivity responses was evaluated using a weight of the evidence approach. A local lymph node assay (LLNA) in mice evaluating concentrations of rupintrivir up to 50% in dimethylformamide showed no evidence of sensitizing capability. An irritation study conducted in rabbits was performed to assess potential dermal irritancy and provide information for worker safety guidelines. The study showed no evidence of skin irritation when the material was placed in direct contact with the skin in a semi-occluded fashion for four days. Quantitative whole body autoradiography (QWBA) following intranasal instillation of the compound into rabbits showed that the compound was retained in the nasal cavity or was swallowed. No radioactivity was observed in the pulmonary regions of these animals. Histopathologic evaluation of the nasopharyngeal tract and the lungs of both rats and dogs exposed by intranasal instillation acutely or following repeated intranasal exposures for 14 (rat) or 28 days (rat and dog) did not reveal any evidence of irritation or inflammation in these regions of the respiratory tract. These data demonstrate that rupintrivir does not cause irritation or inflammatory responses that may precede the development of sensitization of the skin or respiratory tract. It was concluded that the weight of the available toxicologic evidence indicated that rupintrivir was not likely to cause sensitization of either the skin or the respiratory tract in humans following intranasal delivery.

Absence of embryo-fetal toxicity in rats or rabbits following oral dosing with nelfinavir.

The potential for nelfinavir mesylate (VIRACEPT) to induce maternal and embryo-fetal toxicity was evaluated in rats and rabbits following oral administration. The drug was administered by gavage to rats at doses of 200, 500, or 1000mg/kg/day on days 6-17 of gestation and to rabbits at doses of 200, 400, or 1000mg/kg/day on days 7-20 of gestation. Dams and does were euthanized on GD20 and 29, respectively, and the offspring were weighed and examined for external, visceral, and skeletal alterations. Maximum plasma nelfinavir concentrations (C(max)) in rats were comparable to C(max) values in humans and were 3- to 6-fold higher than the reported human trough levels, while plasma nelfinavir levels in rabbits were approximately 0.13-0.17x the human C(max) and 0.25-0.5x the human trough. In rats, no treatment-related maternal or embryo-fetal toxicity was observed at any dose level and the NOAEL for both maternal and fetal toxicity was considered to be 1000mg/kg/day. Two rabbits in the 400mg/kg/day group died prior to scheduled termination. Because no deaths occurred in the high dose group and there were no other treatment-related signs of clinical toxicity in any dose group, these deaths were considered unrelated to nelfinavir. Group mean body weight loss in rabbits was observed at 1000mg/kg/day on gestation days 7-10. Food consumption was also reduced in this treatment group throughout the dosing period. There were no treatment-related findings in other maternal or fetal parameters. Thus, the no-observed-adverse-effect-level (NOAEL) for maternal toxicity in the rabbit was considered to be 400mg/kg/day (based on maternal body weight loss in the high dose group), while the NOAEL for embryo-fetal toxicity in the rabbit was considered to be 1000mg/kg/day. Thus, under the conditions of this study, nelfinavir was not considered to be toxic to the rat or rabbit conceptus.

Absence of reproductive and developmental toxicity in rats following oral dosing with nelfinavir.

The potential for nelfinavir mesylate (VIRACEPT) to produce reproductive toxicity was evaluated in rats administered oral doses of 200, 500, or 1000mg/kg/day. In the fertility and early embryonic development to implantation study, male rats were treated beginning 28 days prior to mating until necropsy and females for 2 weeks prior to mating and through gestation day (GD) 7. In the pre- and postnatal development study, pregnant rats were treated from GD 6 through lactation day (LD) 20. Selected F(1) pups from this study were evaluated in sensory and behavioral tests and were subsequently mated. Pregnant F(1) females were euthanized on GD 20 and their F(2) fetuses were examined. F(1) animals were not directly dosed with the drug. No treatment-related effects were observed on any male reproductive parameters. Administration of nelfinavir did not produce adverse effects on fertility, pregnancy, embryo-fetal development, parturition, or lactation in the F(0) generation. Similarly, no adverse effects of nelfinavir treatment were observed on pre- and postnatal growth, development, reproductive performance and embryo-fetal development in the F(1) offspring. Based on the results of this study, the no-observed-adverse-effect-level (NOAEL) for developmental and reproductive toxicity in rats was considered to be 1000mg/kg/day, the highest dose tested.