Acetochlor-Induced Rat Nasal Tumors: Further Studies on the Mode of Action and Relevance to Humans

Green, T.; Lee, R.; Moore, Ray; Ashby, John; Willis, G; Lund, Valerie J.; Clapp, M. J. L.

doi:10.1006/rtph.2000.1413

Cited by 40 publications

(18 citation statements)

References 5 publications

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“…1996, 1997), when evaluated at the maximum tolerated dose (MTD, <1000 mg/kg). However, at supra‐MTD, it showed significant carcinogenicity to the rat nasal epithelium (Green et al. 2000), increased the chromatid exchange frequency of human lymphocytes (Hill et al.…”

Section: Resultsmentioning

confidence: 99%

Evaluation of insecticidal and genotoxic effects of imidacloprid and acetochlor in Drosophila melanogaster

Frantzios

Paptsiki

Sidiropoulou

et al. 2008

J Applied Entomology

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Two pesticides, the insecticide imidacloprid and the herbicide acetochlor, were evaluated for their insecticidal and genotoxic effects in Drosophila melanogaster. Their insecticidal effects were assessed by calculating LC50 values after acute or chronic exposure of larvae and adults to different concentrations of the test compounds. After acute exposure, the LC50 of imidacloprid was 7.59 × 10−5 M for larvae and 1.43 × 10−4 M for adults, and after chronic exposure, it was 2.67 × 10−5 M and 6.09 × 10−5 M for larvae and adults, respectively. On the contrary, the herbicide acetochlor showed no acute or chronic insecticidal effect against either larvae or adults, even at very high concentrations (8 × 10−3 M). For the evaluation of genotoxic properties of the two pesticides, the Somatic Mutation and Recombination Test in D. melanogaster was used. Our results suggest that neither imidacloprid nor acetochlor exhibits mutagenic or recombinogenic activity at applicable concentrations.

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Section: Resultsmentioning

confidence: 99%

Evaluation of insecticidal and genotoxic effects of imidacloprid and acetochlor in Drosophila melanogaster

Frantzios

Paptsiki

Sidiropoulou

et al. 2008

J Applied Entomology

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“…1 Like another PDEI, 2 RF yields 4-amino-3,5-dichloropyridine (ADCP) as a metabolite, which is structurally similar to other single ring compounds such as 2,6-dimethylaniline (DMA), p-cresidine and alachlor, all of which produce nasal tumors. [3][4][5][6][7] DMA is reported to bind to the DNA of nasal mucosa, 8 whereas alachlor showed no DNA strand breaks by alkaline elution, suggesting the absence of DNA damage. 9 To assess whether RF or its metabolite ORDER REPRINTS ADCP bind to rat nasal mucosal DNA, we used the 32 P-postlabeling assay 10 which is very sensitive and can, under optimal conditions, detect single modified DNA bases (adducts), in 10 9 -10 10 nucleosides per 1-10 mg of DNA as a reliable expression of DNA damage.…”

Section: Introductionmentioning

confidence: 99%

Lack of Dna Binding in the Rat Nasal Mucosa and Other Tissues of the Nasal Toxicants Roflumilast, a Phosphodiesterase 4 Inhibitor, and a Metabolite, 4-Amino-3,5-Dichloropyridine, in Contrast to the Nasal Carcinogen 2,6-Dimethylaniline*

Jeffrey

Luo

Amin

et al. 2002

Drug and Chemical Toxicology

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The phosphodiesterase 4 inhibitor Roflumilast (B9302-107) (RF) and its metabolite 4-amino-3,5-dichloropyridine (ADCP) produced nasal toxicity in preclinical safety studies with rats. The purpose of this study was to assess the possible formation of DNA adducts, by RF and ADCP, in the nasal mucosa, liver and testes of male rats using the 32P-postlabeling assay. For comparison, rats were exposed to the DNA-reactive carcinogens 2,6-dimethylaniline (DMA), also known as 2,6-xylidine, a nasal carcinogen, and the aromatic amine carcinogens 4,4'-methylene-bis(2-chloroaniline) (MOCA), which yields monocyclic DNA adducts, and 2-acetylaminofluorene (2-AAF). In the case of RF, possible sources of DNA adducts include the parent molecule and its ADCP moiety by enzymatic N-hydroxylation and sulfation, reactions typical of carcinogenic aromatic amines. 4-Acetoxylamino-3,5-dichloropyridine (N-acetoxy-ADCP), a chemically activated derivative of ADCP, was prepared and used to modify DNA which was then used to establish the chromatographic conditions with which to reliably detect whether or not such adducts were formed metabolically from RF and ADCP. Similarly, a standard N-hydroxy-DMA was prepared, but the corresponding N-acetoxy derivative was unstable and decomposed during synthesis. Both N-hydroxy-DMA and N-acetoxy-ADCP were mutagenic in the Salmonella typhimurium Ames assay using strain TA100 without an exogenous bioactivation system, with the former being more potent. N-hydroxy-ADCP was essentially inactive in this assay. For the 32P-postlabeling assay, male Wistar rats were exposed to the test substances and carrier control compounds by intragastric instillation at the selected dose levels for 7 days. Subsequently, the nasal mucosa, liver, and testes of the rats exposed to the test or control compounds were extirpated, the DNA extracted and the samples postlabeled. The patterns of adducts formed with the test compounds were compared to those formed in N-acetoxy-ADCP- and N-hydroxy-DMA-adducted DNA, which were assayed by both nuclease P1 and butanol enhancement methods. Based upon the similarity of results from the two enhancement methods, only the former was used for the in vivo studies. No evidence was obtained for the formation of DNA adducts from RF or its metabolites, specifically ADCP, under the conditions of these assays despite the ability to detect adducts from DNA modified chemically with N-acetoxy-ADCP and DNA adducts from the other compounds in their target organs. In the absence of a pattern of compound-related spots, we conclude that RF does not form DNA adducts having the potential to initiate neoplasia in these three tissues.

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“…In human and rat liver microsomes, acetochlor is bioactivated via a multistep pathway to the putative DNA-reactive metabolite, 2-methyl-6-ethylbenzoquinoneimine (Jefferies et al, 1998;Coleman et al, 2000;Green et al, 2000). Exposure to acetochlor has been reported to significantly increase estrogen-binding activity in rat uteri (Rollerova et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Identification of human urinary metabolites of acetochlor in exposed herbicide applicators by high-performance liquid chromatography-tandem mass spectrometry

Barr

Hines

Olsson

et al. 2007

J Expo Sci Environ Epidemiol

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Acetochlor is a preemergent chloroacetanilide herbicide used to control annual grasses and small-seeded broadleaf weeds. It is the second most abundantly applied herbicide on corn crops in the United States; however, human metabolites associated with known exposure to acetochlor have not been positively identified and confirmed. We positively identified acetochlor mercapturate (ACM) as a metabolite of acetochlor in urine samples collected during a 24-h period from custom (commercial) applicators who had applied acetochlor on either the day of or the day before urine collection. Concentrations in applicator urine samples ranged from 0.5 to 449 mg/l (0.3-121 mg/g creatinine). We found that ACM accounted for as much as 42% of the total acetochlor-derived metabolites; however, as the exposure level decreased (based on total acetochlor metabolite level), ACM became a less abundant metabolite of acetochlor (o17%). Unmetabolized acetochlor was also measured in the urine samples analyzed. At high exposures (classified as 4100 mg/l), acetochlor accounted for about 0.8% of the total excreted acetochlor metabolites (B2% of the ACM concentrations). At lower exposures (classified as ACM o10 mg/l), ACM and acetochlor concentrations were similar. Additionally, we tentatively identified another acetochlor metabolite that appeared to be important at low levels of exposure.

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Acetochlor-Induced Rat Nasal Tumors: Further Studies on the Mode of Action and Relevance to Humans

Cited by 40 publications

References 5 publications

Evaluation of insecticidal and genotoxic effects of imidacloprid and acetochlor in Drosophila melanogaster

Evaluation of insecticidal and genotoxic effects of imidacloprid and acetochlor in Drosophila melanogaster

Lack of Dna Binding in the Rat Nasal Mucosa and Other Tissues of the Nasal Toxicants Roflumilast, a Phosphodiesterase 4 Inhibitor, and a Metabolite, 4-Amino-3,5-Dichloropyridine, in Contrast to the Nasal Carcinogen 2,6-Dimethylaniline*

Identification of human urinary metabolites of acetochlor in exposed herbicide applicators by high-performance liquid chromatography-tandem mass spectrometry

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