The NERC and CEH trademarks and logos ('the Trademarks') are registered trademarks of NERC in the UK and other countries, and may not be used without the prior written consent of the Trademark owner. ARs in the U.S. in 1997, 3 (ii) a market analysis suggesting that U. ADVERSE OUTCOME PATHWAY FOR ANTICOAGULANT RODENTICIDES 60An AOP is a conceptual framework portraying existing knowledge as a logical sequence of 61 processes linking a direct molecular initiating event to an adverse effect across multiple levels of 62 biological organization, which is relevant in risk assessment. [17][18][19] In an ecological context, warfarin resistance is at Y139; common mutations include substitutions of S, C, and F, for Y. 119Other common mutations that afford warfarin resistance are indicated in yellow. 9 FGARs (warfarin, chlorophacinone) exceeded levels of concern for non-target birds and 296 mammals. Consumption of SGAR-exposed prey also exceeded levels of concern for predatory 297 birds and mammals. While consumption of FGAR-exposed prey posed a hazard for non-target 298 mammals, levels of concern were rarely exceeded for birds. 4 In some use scenarios (e.g., 299Rozol® for control of prairie dogs, Cynomys ludovicianus), label requirements even state that 300 applicators must make multiple follow-up visits after application to remove dead or dying target 301 species to mitigate hazard to non-target scavengers and predators. 86 UNSOLVED ISSUES 380There are significant unknowns related to exposure and effects to predatory wildlife associated 381 with use of ARs. Among these are basic and applied data needs to supplement risk assessments. 382Some of these data are best derived from controlled exposure trials using captive animals, while 383 other information can only be generated from field observations and hypothesis-driven eco-384 epidemiological studies, and even a combination of these activities. Exposure pathways can be complex, with non-target predators encountering a combination 396 of ARs. Notably, tissues analyzed from mortality incidents document exposure to multiple 397 SGARs to varying degrees, 12,51,52,56,62,63,65,68,71,100 and occasionally even combinations of FGARs 398 and SGARs. 51,56 That suggests that some predators may reside and forage opportunistically at the 399 interface of urban/suburban/rural and agricultural settings. For example, rats and non-target 400 small mammals (but not house mice) exposed to SGARs while indoors may move outdoors from 419In contrast to the aforementioned terrestrial exposure pathway, there is now evidence that 420 warfarin, at nanogram per liter quantities, is detectable in some wastewater effluents. 120 Its 421 source is presumed to be of human origin. However, based on both its low concentration and log 422 K ow (2.37), it is highly unlikely that this is a significant source of exposure for predatory wildlife. hemorrhagic syndrome in chickens, and warfarin sensitivity and resistance in rats, has been 436 studied in great detail, 125 vitamin K status has not been e...

In the United States, new regulatory restrictions have been placed on the use of some second-generation anticoagulant rodenticides. This action may be offset by expanded use of first-generation compounds (e.g., diphacinone; DPN). Single-day acute oral exposure of adult Eastern screech-owls (Megascops asio) to DPN evoked overt signs of intoxication, coagulopathy, histopathological lesions (e.g., hemorrhage, hepatocellular vacuolation), and/or lethality at doses as low as 130 mg/kg body weight, although there was no dose-response relation. However, this single-day exposure protocol does not mimic the multiple-day field exposures required to cause mortality in rodent pest species and non-target birds and mammals. In 7-day feeding trials, similar toxic effects were observed in owls fed diets containing 2.15, 9.55 or 22.6 ppm DPN, but at a small fraction (<5%) of the acute oral dose. In the dietary trial, the average lowest-observed-adverse-effect-level for prolonged clotting time was 1.68 mg DPN/kg owl/week (0.24 mg/kg owl/day; 0.049 mg/owl/day) and the lowest lethal dose was 5.75 mg DPN/kg owl/week (0.82 mg/kg owl/day). In this feeding trial, DPN concentration in liver ranged from 0.473 to 2.21 μg/g wet weight, and was directly related to the daily and cumulative dose consumed by each owl. A probabilistic risk assessment indicated that daily exposure to as little as 3-5 g of liver from DPN-poisoned rodents for 7 days could result in prolonged clotting time in the endangered Hawaiian short-eared owl (Asio flammeus sandwichensis) and Hawaiian hawk (Buteo solitarius), and daily exposure to greater quantities (9-13 g of liver) could result in low-level mortality. These findings can assist natural resource managers in weighing the costs and benefits of anticoagulant rodenticide use in pest control and eradication programs.

In the United States, new regulations on second-generation anticoagulant rodenticides will likely be offset by expanded use of first-generation anticoagulant rodenticides. In the present study, eastern screech-owls (Megascops asio) were fed 10 µg diphacinone/g wet weight food for 7 d, and recovery was monitored over a 21-d postexposure period. By day 3 of exposure, diphacinone (DPN) was detected in liver (1.63 µg/g wet wt) and kidney (5.83 µg/g) and coagulopathy was apparent. By day 7, prothrombin time (PT) and Russell's viper venom time (RVVT) were prolonged, and some individuals were anemic. Upon termination of exposure, coagulopathy and anemia were resolved within 4 d, and residues decreased to <0.3 µg/g by day 7. Liver and kidney DPN elimination occurred in 2 phases (initial rapid loss, followed by slower loss rate), with overall half-lives of 11.7 d and 2.1 d, respectively. Prolonged PT and RVVT occurred in 10% of the exposed owls with liver DPN concentrations of 0.122 µg/g and 0.282 µg/g and in 90% of the owls with liver concentrations of 0.638 µg/g and 0.361 µg/g. These liver residue levels associated with coagulopathy fall in the range of values reported in raptor mortality incidents involving DPN. These tissue-based toxicity reference values for coagulopathy in adult screech-owls have application for interpreting nontarget mortality and assessing the hazard of DPN in rodent-control operations. Diphacinone exposure evokes toxicity in raptors within a matter of days; but once exposure is terminated, recovery of hemostasis occurs rapidly.

No abstract

The osprey (Pandion haliaetus) is a well-known sentinel of environmental contamination, yet no studies have traced pharmaceuticals through the water-fish-osprey food web. A screening-level exposure assessment was used to evaluate the bioaccumulation potential of 113 pharmaceuticals and metabolites, and an artificial sweetener in this food web. Hypothetical concentrations in water reflecting "wastewater effluent dominated" or "dilution dominated" scenarios were combined with pH-specific bioconcentration factors (BCFs) to predict uptake in fish. Residues in fish and osprey food intake rate were used to calculate the daily intake (DI) of compounds by an adult female osprey. Fourteen pharmaceuticals and a drug metabolite with a BCF greater than 100 and a DI greater than 20 mg/kg were identified as being most likely to exceed the adult human therapeutic dose (HTD). These 15 compounds were also evaluated in a 40 day cumulative dose exposure scenario using firstorder kinetics to account for uptake and elimination. Assuming comparable absorption to humans, the half-lives (t 1/2 ) for an adult osprey to reach the HTD within 40 days were calculated. For 3 of these pharmaceuticals, the estimated t 1/2 in ospreys was less than that for humans, and thus an osprey might theoretically reach or exceed the HTD in 3 to 7 days. To complement the exposure model, 24 compounds were quantified in water, fish plasma, and osprey nestling plasma from 7 potentially impaired locations in Chesapeake Bay. Of the 18 analytes detected in water, 8 were found in fish plasma, but only 1 in osprey plasma (the antihypertensive diltiazem). Compared to diltiazem detection rate and concentrations in water (10/12 detects,