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The in vivo formation of covalent aflatoxin B1(AFB,)-DNA adducts within the rRNA gene sequences of nuclear DNA has been studied in AFB,-treated rats. Liver nuclear DNA, enriched in ribosomal DNA (rDNA) by one round of cesium salt density gradient centrifugation, was treated under buffered alkaline conditions to convert unstable AFB,-N7-guanine adducts to stable AFB,-formamidopyrimidine derivatives. The alkali-treated DNA was hybridized to 18S and 28S rRNA in 70% formamide buffer to form rRNA-rDNA hybrids. These hybrids were separated from the bulk of nuclear DNA by two rounds of centrifugation in CsCI, and the level of AFB1 adduction to rDNA versus total nuclear DNA was compared as The irreversibility of tumor initiation, as well as the heritability of the tumor phenotype, have drawn attention to DNA as the critical macromolecular target in chemical carcinogenesis (1, 2). Changes in DNA sequences, brought about by carcinogen-DNA interactions, could constitute molecular bases for observed alterations in gene expression that accompany neoplastic transformation by chemicals (3, 4). Evidence supporting a putative role of carcinogen-induced DNA sequence change in initiating tumor development has been provided by both qualitative and quantitative correlations between the carcinogenic and mutagenic potency exhibited by many carcinogens and the potency of chemicals as carcinogens compared to the total levels of covalent DNA modification observed in treated animals (5-9). Elucidation of the molecular bases for mutation and tumor initiation by carcinogens will require detailed knowledge of DNA modification within specific base sequences that can be related to alterations in gene function. Earlier experiments with this objective have included attempts to relate mutation frequency with DNA adduct formation by mutagens/carcinogens such as benzo[a]pyrene (10) and aflatoxin B1 (AFB1) (11,12). While this approach has provided quantitative data on apparent mutagenic efficiency of various DNA adducts, structural modifications could not be localized within the marker genes in which mutation was scored. Furthermore, this quantitative approach assumes that DNAcarcinogen adducts are randomly distributed. Recent studies have indicated the susceptibility to carcinogen modification is not random but is affected by factors such as transcriptional activity, specific neighboring base composition, and nucleotide sequence (13).We have conducted experiments to investigate the structural and functional impairment of a specific gene sequence, the rRNA gene, by the hepatocarcinogen AFB1. Our experimental design permits simultaneous investigation of chemical damage and repair within an expressed gene as well as the resulting functional impairment in those same gene sequences. AFB1 was used in these studies because products of its reaction with DNA have been thoroughly characterized, and the only known site of reaction is at the N7 position of guanine (14-16). Furthermore, extensive information about AFB1-DNA adduct stability and removal h...

The embryotoxicity of carboxymethyl(tri-methy1)arsonium bromide [arsenobetaine, (CH,),As+CH,COO-] and of 2-hydroxyethyl(tri-methy1)arsonium bromide [arsenocholine, (CH,)&'CH,CH,OH>Br] was explored. Sprague-Dawley rat embryos with intact yolk sacs were removed on day 11 of gestation and grown in a culture medium for 24 h in the presence and absence of rat liver (S-9) homogenate. Solutions of arsenobetaine or arsenocholine in dmethyl sulfoxide [DMSO, (CH,),SO] (0.03 cm3) were added to the media to achieve concentrations of 20 pg arsenic compound per cm' of medium. After 24 h the circulation and heart beat were monitored (indicator of embryolethality); in addition the crown-to-rump lengths were measured and the neural structures (somites) and limb buds observed (indicator of embryotoxicity). No evidence for embryotoxicity or embryolethality was found in the absence or the presence of S-9. These results indicate that arsenobetaine, the most common arsenic compound found in seafood at concentrations from several micrograms to several hundred micrograms arsenic per gram, lacks subacute and acute prenatal toxicity.

Toxic torts are increasing across the country and often the results of the neuropsychological evaluation are crucial for defining damages. Therefore, the accurate differentiation of those damaged by toxic exposure from those exaggerating or fabricating deficits is important. However, there is little research on malingering in this context. Presented are four patients claiming cognitive deficits after apparent occupational neurotoxic exposure who were diagnosed as malingering using the Slick, Sherman, and Iverson criteria. The goals of this article were to (1) illustrate the application of the Slick Criteria; (2) discuss current knowledge about the neurological and neurocognitive effects of toxic substances and its impact on clinical decision-making; (3) discuss the application of the Slick Criteria, specifically, and malingering research, generally, to toxic exposure cases; and (4) propose a paradigm in which medical, toxicological and neuropsychology professionals coordinately evaluate cases of alleged neurotoxic chemical exposure.

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