18 research outputs found
Utility of a next‐generation framework for assessment of genomic damage: A case study using the pharmaceutical drug candidate etoposide
We present a hypothetical case study to examine the use of a next-generation framework developed by the Genetic Toxicology Technical Committee of the Health and Environmental Sciences Institute for assessing the potential risk of genetic damage from a pharmaceutical perspective. We used etoposide, a genotoxic carcinogen, as a representative pharmaceutical for the purposes of this case study. Using the framework as guidance, we formulated a hypothetical scenario for the use of etoposide to illustrate the application of the framework to pharmaceuticals. We collected available data on etoposide considered relevant for assessment of genetic toxicity risk. From the data collected, we conducted a quantitative analysis to estimate margins of exposure (MOEs) to characterize the risk of genetic damage that could be used for decision-making regarding the predefined hypothetical use. We found the framework useful for guiding the selection of appropriate tests and selecting relevant endpoints that reflected the potential for genetic damage in patients. The risk characterization, presented as MOEs, allows decision makers to discern how much benefit is critical to balance any adverse effect(s) that may be induced by the pharmaceutical. Interestingly, pharmaceutical development already incorporates several aspects of the framework per regulations and health authority expectations. Moreover, we observed that quality dose response data can be obtained with carefully planned but routinely conducted genetic toxicity testing. This case study demonstrates the utility of the next-generation framework to quantitatively model human risk based on genetic damage, as applicable to pharmaceuticals
Utility of a next generation framework for assessment of genomic damage: A case study using the industrial chemical benzene
We recently published a next generation framework for assessing the risk of genomic damage via exposure to chemical substances. The framework entails a systematic approach with the aim to quantify risk levels for substances that induce genomic damage contributing to human adverse health outcomes. Here, we evaluated the utility of the framework for assessing the risk for industrial chemicals, using the case of benzene. Benzene is a well‐studied substance that is generally considered a genotoxic carcinogen and is known to cause leukemia. The case study limits its focus on occupational and general population health as it relates to benzene exposure. Using the framework as guidance, available data on benzene considered relevant for assessment of genetic damage were collected. Based on these data, we were able to conduct quantitative analyses for relevant data sets to estimate acceptable exposure levels and to characterize the risk of genetic damage. Key observations include the need for robust exposure assessments, the importance of information on toxicokinetic properties, and the benefits of cheminformatics. The framework points to the need for further improvement on understanding of the mechanism(s) of action involved, which would also provide support for the use of targeted tests rather than a prescribed set of assays. Overall, this case study demonstrates the utility of the next generation framework to quantitatively model human risk on the basis of genetic damage, thereby enabling a new, innovative risk assessment concept. Environ. Mol. Mutagen. 61:94–113, 2020. © 2019 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.JRC.F.3-Chemicals Safety and Alternative Method
Perfluorooctane Sulfonate Plasma Half-Life Determination and Long-Term Tissue Distribution in Beef Cattle (Bos taurus)
Perfluorooctane
sulfonate (PFOS) is used in consumer products as
a surfactant and is found in industrial and consumer waste, which
ends up in wastewater treatment plants (WWTPs). PFOS does not breakdown
during WWTP processes and accumulates in the biosolids. Common practices
include application of biosolids to pastures and croplands used for
feed, and as a result, animals such as beef cattle are exposed to
PFOS. To determine plasma and tissue depletion kinetics in cattle,
2 steers and 4 heifers were dosed with PFOS at 0.098 mg/kg body weight
and 9.1 mg/kg, respectively. Plasma depletion half-lives for steers
and heifers were 120 ± 4.1 and 106 ± 23.1 days, respectively.
Specific tissue depletion half-lives ranged from 36 to 385 days for
intraperitoneal fat, back fat, muscle, liver, bone, and kidney. These
data indicate that PFOS in beef cattle has a sufficiently long depletion
half-life to permit accumulation in edible tissues
Distribution and Excretion of Perfluorooctane Sulfonate (PFOS) in Beef Cattle (<i>Bos taurus</i>)
Perfluorooctane
sulfonate (PFOS), a perfluoroalkyl surfactant used in many industrial
products, is present in industrial wastes and in wastewater treatment
plant biosolids. Biosolids are commonly applied to pastures and crops
used for animal feed; consequently, PFOS may accumulate in the edible
tissues of grazing animals or in animals exposed to contaminated feeds.
There are no data on the absorption, distribution, and excretion of
PFOS in beef cattle, so a 28-day study was conducted to determine
these parameters for PFOS in three Lowline Angus steers given a single
oral dose of PFOS at approximately 8 mg/kg body weight. PFOS concentrations
were determined by liquid chromatography–tandem mass spectrometry
in multiple tissue compartments. The major route of excretion was
in the feces (11 ± 1.3% of the dose, mean ± standard deviation)
with minimal PFOS elimination in urine (0.5 ± 0.07% of the dose).
At day 28 the mean plasma concentration remained elevated at 52.6
± 3.4 μg/mL, and it was estimated that 35.8 ± 4.3%
of the dose was present in the plasma. Plasma half-lives could not
be calculated due to multiple peaks caused by apparent redistributions
from other tissues. These data indicate that after an acute exposure
PFOS persists and accumulates in edible tissues. The largest PFOS
body burdens were in the blood (∼36%), carcass remainder (5.7
± 1.6%), and the muscle (4.3 ± 0.6%). It was concluded that
PFOS would accumulate in edible tissues of beef, which could be a
source of exposure for humans
Absorption and Excretion of <sup>14</sup>C-Perfluorooctanoic Acid (PFOA) in Angus Cattle (Bos taurus)
Perfluoroalkyl substances (PFASs), such as perfluorooctanoic
acid
(PFOA), are environmentally persistent industrial chemicals often
found in biosolids. Application of these biosolids to pastures raises
concern about the accumulation of PFOA in the edible tissues of food
animals. Because data on the absorption, distribution, metabolism,
and excretion (ADME) of PFOA in cattle were unavailable, a study was
conducted to determine pharmacokinetic parameters following a single
oral exposure (1 mg/kg body weight of <sup>14</sup>C-PFOA) in four
Lowline Angus steers. Radiocarbon was quantified in blood, urine,
and feces for 28 days and in tissues at the time of slaughter (28
days) by liquid scintillation counting (LSC) or by combustion analysis
with LSC with confirmation by liquid chromatography–tandem
mass spectrometry (LC-MS/MS). <sup>14</sup>C-PFOA was completely absorbed
and excreted (100.7 ± 3.3% recovery) in the urine within 9 days
of dosing. The plasma elimination half-life was 19.2 ± 3.3 h.
No <sup>14</sup>C-PFOA-derived radioactivity was detected in edible
tissues. Although PFOA was rapidly absorbed, it was also rapidly excreted
by steers and did not persist in edible tissues, suggesting meat from
cattle exposed to an acute dose of PFOA is unlikely to be a major
source of exposure to humans