Predictive Assessment of the Aquatic Toxicity of Multiple Chemical Mixtures

Abstract. Pharmaceuticals and other contaminants of emerging concern present unique challenges to environmental risk assessment and management. Fortunately, mammalian pharmacology and toxicology safety data are more readily available for pharmaceuticals than other environmental contaminants. Identifying approaches to read-across such pharmaceutical safety information to non-target species represents a major research need to assess environmental hazards. Here, we tested a biological readacross hypothesis from emergency medicine with common aquatic invertebrate and vertebrate models. In mammals, the antihistamine diphenhydramine (DPH) confers protection from poisoning by acetylcholinesterase inhibition because DPH blocks the acetylcholine receptor. We employed standardized toxicity methods to examine individual and mixture toxicity of DPH and the acetylcholinesterase inhibitor diazinon (DZN) in Daphnia magna (an invertebrate) and Danio rerio (zebrafish, a vertebrate). Though the standardized Fish Embryo Toxicity method evaluates early life stage toxicity of zebrafish (0-3 days post fertilization, dpf), we further evaluated DPH, DZN, and their equipotent mixture during three development stages (0-3, 3-6, 7-10 dpf) in zebrafish embryos. Independent action and concentration addition mixture models and fish plasma modeling were used to assist interpretation of mixture toxicity experiments. Though our primary hypothesis was not confirmed in acute studies with Daphnia magna, DPH conferred a protective effect for acute DZN toxicity to zebrafish when DPH plasma levels were expected to be greater than mammalian therapeutic, but lower than acutely lethal, internal doses. We further observed that timing of developmental exposure influenced the magnitude of DZN and DPH toxicity to zebrafish, which suggests that future zebrafish toxicity studies with pharmaceuticals and pesticides should examine exposure during developmental stages.KEY WORDS: alternative toxicity test methods; biological read-across; comparative pharmacology and toxicology; mixture toxicology; pharmaceuticals in the environment.

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“…Conversely, the IA model predicts the interaction of dissimilarly acting toxicants (34,35) and was first proposed by Bliss in 1939 (Eq. 2):…”

Section: Mixture Modelsmentioning

confidence: 99%

Comparative Pharmacology and Toxicology of Pharmaceuticals in the Environment: Diphenhydramine Protection of Diazinon Toxicity in Danio rerio but Not Daphnia magna

Kristofco

Chambliss

et al. 2014

AAPS J

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“…Several studies have shown that the combined effects of pesticides sharing a common mode of toxic action are best predicted by a concentration addition (CA) model (Faust et al 2000;Deneer 2000;Kudsk et al 2005;Belden et al 2007). According to the CA model, pesticide concentrations are first normalized for potency and then the total concentration of the mixture is calculated and used to predict mixture toxicity (Faust et al 2000).…”

Section: Estimating the Effects Of Mixtures Of Carbamate And Organophmentioning

confidence: 99%

Risks of carbamate and organophosphate pesticide mixtures to salmon in the Pacific Northwest

Moore¹,

Teed

2012

Integr Envir Assess & Manag

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Salmon populations in the Pacific Northwest are being affected by a variety of environmental stressors including intense fishing pressure, parasites and disease, climatic variability and change, land development, hatchery production, hydropower operations, stormwater runoff, and exposure to toxic contaminants. In recent years, there has been much concern that mixtures of pesticides are causing toxic effects to Pacific salmon. In this study, we compared measured stream water concentrations from 2 monitoring studies conducted in the Pacific Northwest with concentration-response curves derived for inhibition of brain acetylcholinesterase activity in juvenile coho salmon (Oncorhynchus kisutch) for mixtures of organophosphate (OPs) and carbamate (CBs) pesticides. In the first monitoring study, samples were collected from 2003 to 2007 in salmonid-bearing waters of 5 urban or agricultural watersheds in Washington State. This study was targeted to areas of high pesticide use and generally involved weekly sampling during the pesticide use season. The second monitoring study was the United States Geological Survey National Water Quality Assessment that included samples taken from 2003 to 2010 in California, Idaho, Oregon, and Washington. OPs and CBs were frequently detected in both studies. The available monitoring data collected since 2003, however, demonstrates that mixtures of OPs and CBs in surface waters rarely occur at levels capable of producing significant physiological and behavioral effects in Pacific salmon. The observed mixtures never reached concentrations capable of causing mortality. We conclude that mixtures of organophosphates and carbamates do not pose a significant direct risk to Pacific salmon. Integr Environ Assess Manag 2013;9:70-78. ß 2012 SETAC

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“…Furthermore, ponds and pools are the preferred habitat of many amphibians, which are experiencing worldwide population declines for a variety of hypothesized reasons, including exposure to insecticides [11,12]. Amphibian populations are often exposed to a number of insecticides that vary in their chemical and toxic properties [13]. Moreover, amphibian tolerance to pesticides can be highly enigmatic, with tremendous variation across amphibian families [14], among species within families, and among populations [15].…”

Section: Introductionmentioning

confidence: 99%

Cross‐tolerance in amphibians: Wood frog mortality when exposed to three insecticides with a common mode of action

Hua

Cothran

Stoler

et al. 2013

Enviro Toxic and Chemistry

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Abstract-Insecticide tolerance and cross-tolerance in nontarget organisms is often overlooked despite its potential to buffer natural systems from anthropogenic influence. We exposed wood frog tadpoles from 15 populations to three acetylcholine esterase-inhibiting insecticides and found widespread variation in insecticide tolerance and evidence for cross-tolerance to these insecticides. Our results demonstrate that amphibian populations with tolerance to one pesticide may be tolerant to many other pesticides. Environ. Toxicol. Chem. 2013;32:932-936. # 2013 SETAC

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Predictive Assessment of the Aquatic Toxicity of Multiple Chemical Mixtures

Cited by 121 publications

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Comparative Pharmacology and Toxicology of Pharmaceuticals in the Environment: Diphenhydramine Protection of Diazinon Toxicity in Danio rerio but Not Daphnia magna

Comparative Pharmacology and Toxicology of Pharmaceuticals in the Environment: Diphenhydramine Protection of Diazinon Toxicity in Danio rerio but Not Daphnia magna

Risks of carbamate and organophosphate pesticide mixtures to salmon in the Pacific Northwest

Cross‐tolerance in amphibians: Wood frog mortality when exposed to three insecticides with a common mode of action

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