Application of Bayesian population physiologically based pharmacokinetic (PBPK) modeling and Markov chain Monte Carlo simulations to pesticide kinetics studies in protected marine mammals: DDT, DDE, and DDD in harbor porpoises.

Physiologically based pharmacokinetic (PBPK) modeling in marine mammals is a challenge because of the lack of parameter information and the ban on exposure experiments. To minimize uncertainty and variability, parameter estimation methods are required for the development of reliable PBPK models. The present study is the first to develop PBPK models for the lifetime bioaccumulation of p,p'-DDT, p,p'-DDE, and p,p'-DDD in harbor porpoises. In addition, this study is also the first to apply the Bayesian approach executed with Markov chain Monte Carlo simulations using two data sets of harbor porpoises from the Black and North Seas. Parameters from the literature were used as priors for the first "model update" using the Black Sea data set, the resulting posterior parameters were then used as priors for the second "model update" using the North Sea data set. As such, PBPK models with parameters specific for harbor porpoises could be strengthened with more robust probability distributions. As the science and biomonitoring effort progress in this area, more data sets will become available to further strengthen and update the parameters in the PBPK models for harbor porpoises as a species anywhere in the world. Further, such an approach could very well be extended to other protected marine mammals.

Comparison of bioaccumulation and biomarker responses in Dreissena polymorpha and D. bugensis after exposure to resuspended sediments.

The zebra mussel Dreissena polymorpha is widely used as sentinel organism for the assessment of environmental contamination in freshwater environments. However, in the River Rhine (Germany), the D. polymorpha population is declining, whereas the closely related quagga mussel D. bugensis is found in high numbers at some sites. In the present laboratory study, D. polymorpha and D. bugensis were exposed to resuspended native sediments for ≤2 weeks. Wet sediments (<63 µm, 100 mg l(-1) dry weight) were used as surrogate suspended particulate matter to mimic one of the mussels' main uptake route for chemicals. The sediments were sampled in (1) the River Elbe in Dessau, a site known to be highly polluted with, e.g., organochlorine (OC) pesticides and (2) at a relatively unpolluted site in Havelberg in the River Havel, one of the Elbe's tributaries. Chemical analysis of persistent OC compounds (seven polychlorinated biphenyls [PCBs], DDT and its metabolites (DDX), hexachlorocylohexanes [HCHs], and hexachlorobenzene [HCB]) in soft tissue of mussels showed significantly greater values of PCBs 101, 118, 153, 138, 180, the sum of seven PCBs, and p,p'-DDD in D. bugensis compared with D. polymorpha. Fourteen days of exposure to Dessau sediment increased the concentration of p,p'-DDE and p,p'-DDD, as well as the sum of DDX, in both species compared with Havelberg sediment. Interspecific differences were less pronounced when regarding chemical concentrations with lipid content instead of dry-weight of tissue because D. bugensis had greater levels of total lipid than D. polymorpha. DNA damage in gills, as measured with the comet assay, was greater in D. bugensis compared with D. polymorpha. Simultaneously, the content of heat-shock protein (hsp70) in gills was greater in D. polymorpha than in D. bugensis. DNA damage and hsp70 were not induced by exposure time or sediment type. This study shows that D. bugensis and D. polymorpha may differ in their bioaccumulation potential of OC pesticides as well as their levels of DNA damage and hsp70. Therefore, more investigations are needed before quagga mussel can be used as alternative test organism for the zebra mussel.

DDTs in rice frogs (Rana limnocharis) from an agricultural site, South China: tissue distribution, biomagnification, and potential toxic effects assessment.

Contamination with agricultural pesticides such as dichlorodiphenyltrichloroethane (DDT) and its metabolites, dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), is among several proposed stressors contributing to the global declines in amphibian populations and species biodiversity. These chemicals were examined in insects and in the muscle, liver, and eggs of rice frogs (Rana limnocharis) from the paddy fields of an agricultural site in South China. The ΣDDT (sum of DDT, DDE, and DDD) concentrations ranged from 154 to 915, 195 to 1,400, and 165 to 1,930 ng/g lipid weight in the muscle, liver, and eggs, respectively. All the DDTs (DDT, DDE, and DDD) showed higher affinity for the liver relative to muscle tissue and can be maternally transferred to eggs in female frogs. The average biomagnification factors for DDTs ranged from 1.6 to 1.9 and 1.5 to 2.9 in female and male frogs, respectively, providing clear evidence of their biomagnification from insects to frogs. Compared with the reported DDT levels demonstrated to have toxic effects on frogs, DDTs in the present frogs are unlikely to constitute an immediate health risk. However, the adverse impacts of high DDT residues in eggs on the hatching success and their potential toxicity to the newly metamorphosed larval frogs should be assessed further.

Biomonitoring equivalents for DDT/DDE.

Biomonitoring Equivalents (BEs) are defined as the concentration or range of concentrations of a chemical or its metabolite in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guideline such as a reference dose (RfD) or tolerable daily intake (TDI). BE values can be used as a screening tool for the evaluation of population-based biomonitoring data in the context of existing risk assessments. This study reviews available health based risk assessments and exposure guidance values for DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, CAS #50-29-3) and related metabolites and degradation products DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethane, CAS #72-55-90) and DDD (1,1-dichloro-2,2-bis(p-chloro-phenyl)ethane) based on both non-cancer and cancer risk assessments from the Food and Agriculture Organization/World Health Organization (FAO/WHO), the United States Environmental Protection Agency (US EPA), and other organizations. Laboratory data on distribution and toxicokinetics of DDT and metabolites and estimates of human elimination half-lives were used to estimate BE values (lipid-adjusted blood, serum, or plasma concentrations) corresponding to the various non-cancer exposure guidance values and cancer risk-specific doses. The BE values based on non-cancer risk assessments range from 5000 to 40,000ng/g lipid for the sum of DDT, DDE, and DDD. The BE values corresponding to a 1E-05 cancer risk level for DDT and DDE based on the US EPA assessment are 300 and 500ng/g lipid, respectively. Sources of uncertainty relating to both the basis for the BE values and their use in evaluation of biomonitoring data are discussed. The BE values derived here can be used as a screening tools for evaluation of population biomonitoring data for DDT and related compounds in the context of the existing risk assessment and can assist in prioritization of the potential need for additional risk assessment efforts for DDT relative to other chemicals.

Uptake, elimination, and biotransformation of aqueous and dietary DDT in marine fish.

To understand the biokinetics and potential risks of p,p'-dichlorodiphenyltrichloroethane (DDT) and its metabolites, p,p'-dichlorodiphenyldichloroethylene (DDE) and p,p'-dichlorodiphenyldichloroethane (DDD), in fish, we exposed the black sea breams (Acanthopagrus schlegeli) to aqueous and dietary DDTs and then evaluated the bioaccumulation, distribution, biotransformation, and elimination of DDTs under controlled laboratory conditions. The fish rapidly accumulated DDTs from both routes of exposure, particularly the gills and viscera. Elimination of DDTs following aqueous or dietary uptake was slow, and biotranslocation of DDTs was significant during the exposure period but negligible during the depuration period. The biotransformation process was more significant following dietary exposure. During depuration, DDE was the major biotransformed product in the sea breams' carcasses while DDD was the major product in the gills and viscera. However, DDD had a significantly higher elimination rate than DDE and, subsequently, the fish retained more DDE in the body. Intraspecies variability in the elimination and biotransformation processes in fish was observed. We demonstrated that the route of exposure significantly affected the fate and biokinetics of DDTs in fish. The application of a dynamic model provided a tool for quantifying the elimination and biotransformation of DDT in fish. The present study provided insights into the bioaccumulation and biotransformation pathways of DDT in fish that could have important ecotoxicological implications.

Bioavailability to grains of rice of aged and fresh DDD and DDE in soils.

DDT had been widely used around the world before 1980s and is still under production and use for non-agricultural purposes in China. Because of their special physicochemical properties, p,p'-DDT and its main metabolites, p,p'-DDD and p,p'-DDE, accumulated and persisted in the environment, presenting potential menace on biota. A green-house study was conducted to determine the bioavailability of p,p'-DDD and p,p'-DDE to grains of rice and the influences of traditional Chinese farming practices on their bioaccumulation. Paddy rice and dry rice were grown in submerged paddy soils and non-submerged upland soils, respectively. Two types of soil, Hydragric Anthrosols (An) and Hydragric Acrisols (Ac), were employed. Bioaccumulation factors (BAFs) of DDE ranged from 0.67 for rice grown in non-submerged An to 0.84 in submerged An in the control group, whilst BAFs were all below 0.04 in experimental groups. BAFs of DDD varied from 1.39 for submerged An to 2.26 for submerged Ac in original soils. In contrast, BAFs were between 0.05 for non-submerged Ac and 0.08 for submerged An in DDD-contaminated soils. Flooding seemed to have two contradictory effects on the DDE/DDD accumulation by rice: on one hand, it made the pollutants more mobile and bioavailable; while on the other hand, it enhanced the degradation and binding of POPs. Adding rice straw to the soils protected DDE from being taken up yet promoted DDD accumulation by rice. Furthermore, the distinct inorganic component of the soils might also play an important role in the environmental activities of POPs.

Selective bioaccumulation of chlorinated pesticides and metabolites in Arctic seabirds.

Chlorinated pesticides and metabolites (CPs) were quantified in the seabird species: little auk (Alle alle), Brünnich's guillemot (Uria lomvia), black guillemot (Cepphus grylle) and black-legged kittiwake (Rissa tridactyla). The purpose was to evaluate avian accumulation of selected CPs based on their concentrations and relative patterns, their relation to dietary descriptors (stable isotopes of carbon and nitrogen), to enzymes involved in biotransformation, as well as CPs' accumulation potential relative to the recalcitrant polychlorinated biphenyl PCB-153. In all species, the CP pattern was dominated by p,p'-dichlorodiphenyltrichloroethane (DDE) and hexachlorbenzene (HCB). Except for HCB, concentrations were not related to trophic position. Most CPs were quantified in black guillemot, indicating a slower elimination compared to other seabird species. Brünnich's guillemot showed efficient elimination of chlordanes, whereas the opposite was found for little auk. Kittiwake showed higher accumulation of persistent CP and metabolites than auks, whereas accumulation of less recalcitrant CPs was low.

Comparison of chemical approaches for assessing bioavailability of sediment-associated contaminants.

Two chemical approaches, Tenax extraction and matrix solid-phase microextraction (matrix-SPME), were compared to assess the bioavailability of hydrophobic contaminants from sediment. Hexachlorobiphenyl, DDE, permethrin, chlorpyrifos, and phenanthrene were individually spiked into two sediments differing in physical characteristics. Bioaccumulation was determined by exposing the oligochaete, Lumbriculus variegatus, to the spiked sediments. The rapidly desorbing fraction from Tenax extraction at 6 h and fiber concentration at 14 d from the matrix-SPME were compared for predicting bioaccumulation. Further, a comparison between laboratory-spiked and field-contaminated sediments was conducted. A regression between the rapidly desorbed sediment concentration at 6 h and the amount bioaccumulated across compounds and sediments described 94% of the variation in the data when phenanthrene was excluded. Phenanthrene was excluded because of complications due to a combination of biotransformation and rapid elimination during the sampling process. Contaminant accumulation by L. variegatus also correlated well with matrix-SPME fiber concentrations, accounting for 92% of the variation in the data, again excluding phenanthrene. Both chemical methods provided matrix- and chemical-independent estimations of bio-accumulation for hydrophobic contaminants without extensive biotransformation.

Temporal bioavailability of organochlorine pesticides and PCBs.

Because PCBs and organochlorine pesticides continue to be of global concern, studies that address information gaps, such as factors and influences of spatial and temporal effects on contaminant bioavailability, are valuable. The present study focused on the spatial and temporal distribution of bioavailable organochlorine pesticides and PCBs in surface waters of a contaminated harbor. Passive sampling devices were intensively deployed adjacent to various land uses on the Willamette River, OR, including Portland Harbor and McCormick and Baxter Superfund sites, during summer and fall, extreme conditions, 2001-2004. An increase of bioavailable sigmaDDTs (sum of p,p'-DDT, p,p'-DDD, and p,p'-DDE) concentrations was strongly affected bythe local historic production of DDTs and temporal changes in river conditions. The increase of bioavailable p,p'-DDD and high DDD/DDE ratios observed during summer indicates conditions favoring anaerobic reductive processes. In contrast to sigmaDDTs, the bioavailable concentrations and daily loads of dieldrin and PCBs increased during fall, especially during episodic rainstorms. On the basis of the PCB congener profiles, PCB inputs from urban runoff /sewer overflows were considered likely current sources of bioavailable PCB into the Harbor. The exceedence of the U.S. national and Oregon water quality criteria was a function of the temporal variability of each bioavailable contaminant. This illustrates the impacts associated with temporal changes of bioavailable organochlorine distributions in surface waters and the significance of considering realistic temporal, bioavailability, and site-specific conditions in risk assessment and water quality management.

Metabolic conversion of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD) to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) in the male F344/NCr Rat.

1,1-Dichloro-2,2-bis(p-chlorophenyl)ethane (DDD) and 1,1-dichloro-2, 2-bis(p-chlorophenyl)ethylene (DDE) levels were measured by capillary gas chromatography with electron capture detection in liver and blood serum of male F344/NCr rats exposed for 2 weeks to DDD at dietary concentrations ranging from 8.51 ppm to 2,000 ppm. DDD burdens in serum ranged from <0.006 microM (limit of detection) in control rats to 1.1 microM in the rats fed DDD at 2,000 ppm. The corresponding liver burdens in these animals ranged from <0.006 micromol/kg liver (controls) to 11 micromol/kg liver in rats fed DDD at 2,000 ppm. Levels of DDE in serum or liver were undetectable (<0. 006 microM in serum; <0.006 micromol/kg liver) in rats fed control diet or diet containing 8.51 or 25.5 ppm DDD. The liver and serum burdens of DDE increased with dietary DDD concentration, reaching a maximum of 0.53 microM in serum and 4.7 micromol/kg liver in rats fed 2,000 ppm DDD. As a percentage of total DDD equivalents detected in liver or serum, the DDE burdens increased to a maximum of 36% and 31% in the serum and liver, respectively, of rats fed 689 ppm DDD. The possibility that the DDE might have been generated artifactually in the diet prior to administration to the rats was ruled out by analysis with capillary gas chromatography of the diet containing 2, 000 ppm DDD. The identification of DDE as a metabolite in liver extracts of rats fed 2,000 ppm DDD was confirmed with GC-MS. The results confirmed the presence of DDE as a metabolite of DDD.

Oxidation at C-1 controls the cytotoxicity of 1,1-dichloro-2,2- bis(p-chlorophenyl)ethane by rabbit and human lung cells.

Isolated rabbit Clara cells and a transformed human bronchial epithelial cell line, BEAS-2B, were used to investigate the mechanism of cytotoxicity of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane (DDD), a persistent insecticide and stable metabolite of 1,1,1-trichloro-2,2- bis(p-chlorophenyl)ethane. Both BEAS-2B cells and rabbit Clara cells were highly susceptible to DDD toxicity and were partially protected by 1-aminobenzotriazole, a suicide substrate inhibitor of cytochrome P450 enzymes. DDD (0.05 mM) killed 47 +/- 1.8% of rabbit Clara cells and 42 +/- 7.9% of BEAS-2B cells after 3 hr and 84 +/- 3.0% of rabbit Clara cells and 80 +/- 14% of BEAS-2B cells after 6 hr. Consequently, DDD is the most potent Clara cell toxicant recognized to date. The cytotoxicity of DDD to these cells was decreased by deuterium substitution at the C-1 position. Rabbit Clara cells and pulmonary microsomes incubated with 14C-DDD produced the fully oxidized acetic acid metabolite 2,2'-bis(p- chlorophenyl)acetic acid (DDA), but DDA was not formed by Clara cells when DDD was coincubated with 1-aminobenzotriazole. These results support the hypothesis that the cytotoxicity of DDD to susceptible subpopulations of rabbit and human lung cells is, at least in part, caused by cytochrome P450-mediated oxidation of DDD at C-1. A required step for the production of the cytotoxic intermediate is proposed to be the formation of a highly reactive acyl halide intermediate that is readily hydrolyzed to a stable, nontoxic metabolite, DDA.