Interspecies Dose Extrapolation for Inhaled Dimethyl Sulfate: A PBPK Model-Based Analysis using Nasal Cavity N7-Methylguanine Adducts

Dimethyl sulfate (DMS) is a volatile sulfuric acid ester used principally as a methylating agent in a wide variety of industrial applications. DMS reacts with organic macromolecules by a SN2 mechanism. The weight of experimental evidence suggests that DMS possesses genotoxic and carcinogenic potential. Inhalation studies have shown that repeated exposure to DMS leads to tumors in the nasal cavity and lower respiratory tract in both rats and mice. Here we present a quantitative assessment for cross-species dose extrapolation for inhaled DMS using a physiologically based pharmacokinetic (PBPK) model. The model is designed to simulate N7-methylguanine (N7mG) DNA adduct levels in the nasal mucosa following DMS exposure in rats and humans. This model was parameterized and predictions were tested by comparison against experimentally measured N7mG DNA adduct levels in rat nasal mucosa following inhalation exposure to DMS. The model-based interspecies dose comparison, using N7mG adduct levels in the nasal respiratory tissue as the appropriate dose metrics, predicts a dose rate seven times higher in rats compared to humans.

[1]  P. Ohlin,et al.  Nasal mucosal blood flow at rest and during exercise. , 1985, Acta oto-laryngologica.

[2]  M. D. Topal,et al.  Excision repair of O6-methylguanine synthesized at the rat H-ras N-methyl-N-nitrosourea activation site and introduced into Escherichia coli. , 1989, Carcinogenesis.

[3]  W. Lutz,et al.  Dose-response relationships in chemical carcinogenesis: superposition of different mechanisms of action, resulting in linear-nonlinear curves, practical thresholds, J-shapes. , 1998, Mutation research.

[4]  A. Natarajan,et al.  DNA damage and repair in somatic and germ cells in vivo. , 1995, Mutation research.

[5]  D. Segerbäck,et al.  Propylene oxide: mutagenesis, carcinogenesis and molecular dose. , 1997, Mutation research.

[6]  G. Hoffmann.  Genetic effects of dimethyl sulfate, diethyl sulfate, and related compounds. , 1980, Mutation research.

[7]  P. Magee,et al.  Nitrosamine-induced carcinogenesis. The alklylation of nucleic acids of the rat by N-methyl-N-nitrosourea, dimethylnitrosamine, dimethyl sulphate and methyl methanesulphonate. , 1968, The Biochemical journal.

[8]  Matthew S. Bogdanffy,et al.  Dimethyl sulfate uptake and methylation of DNA in rat respiratory tissues following acute inhalation. , 1995 .

[9]  R. Conolly,et al.  Simulation modeling of the tissue disposition of formaldehyde to predict nasal DNA-protein cross-links in Fischer 344 rats, rhesus monkeys, and humans. , 2000, Environmental health perspectives.

[10]  G. Holmquist,et al.  Heterogeneous repair of N-methylpurines at the nucleotide level in normal human cells. , 1998, Journal of molecular biology.

[11]  S. Bain.  Pathology of the Fischer Rat — Reference and Atlas , 1991, Pathology.

[12]  O R Moss,et al.  DNA-protein cross-links and cell replication at specific sites in the nose of F344 rats exposed subchronically to formaldehyde. , 1994, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[13]  D. G. Gosslee,et al.  Ethylene oxide dose and dose-rate effects in the mouse dominant-lethal test. , 1986, Environmental mutagenesis.

[14]  A. Weston,et al.  Human DNA adduct measurements: state of the art. , 1996, Environmental health perspectives.

[15]  M E Andersen,et al.  Dosimetric adjustment factors for methyl methacrylate derived from a steady-state analysis of a physiologically based clearance-extraction model. , 1999, Inhalation toxicology.

[16]  A Sato,et al.  Partition coefficients of some acetate esters and alcohols in water, blood, olive oil, and rat tissues. , 1994, Occupational and environmental medicine.

[17]  R. J. Purrott,et al.  The effect of changes in dose rate on the yield of chromosome aberrations in human lymphocytes exposed to gamma radiation. , 1976, Mutation research.

[18]  R. Newbold,et al.  Mutagenicity of carcinogenic methylating agents is associated with a specific DNA modification , 1980, Nature.

[19]  E. Dogliotti,et al.  Evidence for AP site formation related to DNA-oxygen alkylation in CHO cells treated with ethylating agents. , 1990, Mutation research.

[20]  W. Russell,et al.  Radiation Dose Rate and Mutation Frequency , 1958, Science.

[21]  G. Felsenfeld,et al.  Reaction of nucleosome DNA with dimethyl sulfate. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[22]  D. Kokkinakis,et al.  The significance of DNA damage, its repair and cell proliferation during carcinogen treatment in the initiation of pancreatic cancer in the hamster model. , 1993, Cancer research.

[23]  P. Emmelot,et al.  Kinetics of induction and growth of precancerous liver-cell foci, and liver tumour formation by diethylnitrosamine in the rat. , 1975, European journal of cancer.

[24]  L. Rhomberg,et al.  Quantitative estimation of the genetic risk associated with the induction of heritable translocations at low‐dose exposure: Ethylene oxide as an example , 1990, Environmental and molecular mutagenesis.

[25]  J. Read.  Excision repair. , 1970, The British journal of radiology.

[26]  J. Swenberg,et al.  DNA adducts: biological markers of exposure and potential applications to risk assessment. , 1996, Mutation research.

[27]  M E Andersen,et al.  A biologically based risk assessment for vinyl acetate-induced cancer and noncancer inhalation toxicity. , 1999, Toxicological sciences : an official journal of the Society of Toxicology.

[28]  J. Morris.  A method for measuring upper respiratory tract vapor uptake and its applicability to quantitative inhalation risk assessment. , 1999, Inhalation toxicology.

[29]  M. Delp,et al.  Physiological Parameter Values for Physiologically Based Pharmacokinetic Models , 1997, Toxicology and industrial health.

[30]  C B Frederick,et al.  Application of a hybrid computational fluid dynamics and physiologically based inhalation model for interspecies dosimetry extrapolation of acidic vapors in the upper airways. , 1998, Toxicology and applied pharmacology.

[31]  C B Frederick,et al.  Application of a hybrid CFD-PBPK nasal dosimetry model in an inhalation risk assessment: an example with acrylic acid. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[32]  Ravi P. Subramaniam Regina B. Richa.  COMPUTATIONAL FLUID DYNAMICS SIMULATIONS OF INSPIRATORY AIRFLOW IN THE HUMAN NOSE AND NASOPHARYNX , 1998 .

[33]  D. Ramotar.  The apurinic-apyrimidinic endonuclease IV family of DNA repair enzymes. , 1997, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[34]  G. Margison,et al.  Mechanisms of carcinogenesis induced by alkylating agents. , 1985, Biochimica et biophysica acta.

[35]  R. Peto,et al.  Initiation and promotion at different ages and doses in 2200 mice. III. Linear extrapolation from high doses may underestimate low-dose tumour risks. , 1981, British Journal of Cancer.

[36]  Julia S. Kimbell,et al.  COMPUTATIONAL FLUID DYNAMICS SIMULATIONS OF INSPIRATORY AIRFLOW IN THE HUMAN NOSE AND NASOPHARYNX , 1998 .

[37]  L. Loeb,et al.  Mutagenesis by apurinic/apyrimidinic sites. , 1986, Annual review of genetics.

[38]  R. Sarangapani,et al.  Analysis of vinyl acetate metabolism in rat and human nasal tissues by an in vitro gas uptake technique. , 1998, Toxicological sciences : an official journal of the Society of Toxicology.

[39]  K T Morgan,et al.  Computer simulation of inspiratory airflow in all regions of the F344 rat nasal passages. , 1997, Toxicology and applied pharmacology.

[40]  M. Andersen,et al.  Physiologically based modeling of vinyl acetate uptake, metabolism, and intracellular pH changes in the rat nasal cavity. , 1997, Toxicology and applied pharmacology.

[41]  Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide. Proceedings of the IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, France, 17-24 February 1998. , 1999, IARC monographs on the evaluation of carcinogenic risks to humans.

[42]  Chung-Xiou Wang,et al.  Diethylnitrosamine exposure-responses for DNA ethylation, hepatocellular proliferation, and initiation of carcinogenesis in rat liver display non-linearities and thresholds , 1999, Archives of Toxicology.

[43]  J A Swenberg,et al.  Dose-response relationships for carcinogens. , 1995, Toxicology letters.

[44]  S. Belinsky,et al.  Accumulation and persistence of DNA adducts in respiratory tissue of rats following multiple administrations of the tobacco specific carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone. , 1986, Cancer research.

[45]  W. Xiao,et al.  Defects in base excision repair combined with elevated intracellular dCTP levels dramatically reduce mutation induction in yeast by ethyl methanesulfonate and N‐methyl‐N′‐nitro‐N‐nitrosoguanidine , 1998, Environmental and molecular mutagenesis.

[46]  D. Beranek.  Distribution of methyl and ethyl adducts following alkylation with monofunctional alkylating agents. , 1990, Mutation research.

[47]  S. Frame,et al.  DNA Methylation, Cell Proliferation, and Histopathology in Rats Following Repeated Inhalation Exposure to Dimethyl Sulfate , 2004, Inhalation toxicology.

[48]  K. Kamiya,et al.  Evidence that carcinogenesis involves an imbalance between epigenetic high-frequency initiation and suppression of promotion. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[49]  K. Hemminki,et al.  Endogenous and background DNA adducts by methylating and 2-hydroxyethylating agents. , 1999, Mutation research.

[50]  P. D. Lawley,et al.  Alkylation of deoxyribonucleic acid by carcinogens dimethyl sulphate, ethyl methanesulphonate, N-ethyl-N-nitrosourea and N-methyl-N-nitrosourea. Relative reactivity of the phosphodiester site thymidylyl(3'-5')thymidine. , 1978, The Biochemical journal.

[51]  S. Kyrtopoulos,et al.  DNA adducts in humans after exposure to methylating agents. , 1998, Mutation research.

[52]  V L Roggli,et al.  Cell number and distribution in human and rat airways. , 1994, American journal of respiratory cell and molecular biology.

[53]  Overall evaluations of carcinogenicity: an updating of IARC Monographs volumes 1 to 42. , 1987, IARC monographs on the evaluation of carcinogenic risks to humans. Supplement.

[54]  Edward L Cussler,et al.  Diffusion: Mass Transfer in Fluid Systems , 1984 .

[55]  W. Mattes.  Use of [8-3H]guanine-labeled deoxyribonucleic acid to study alkylating agent reaction kinetics and stability. , 1992, Analytical biochemistry.