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Glossary ACTIVATING ENZYMES Enzymes or enzyme complexes associated with acti- vation of a xenobiotic compound. Such enzymes typically oxidize the com- pound to reactive intermediates or detoxify the compound. ADDUCT A chemical addition product. For example, when the mutagenic al- kylating agent ethyl methanesulfonate reacts with DNA, any of the normal bases in DNA (i.e., adenine, thymine, guanine, and cytosine) may be con- verted into adducts, such as N7-ethylguanine and N3-ethylcytosine. Adducts may also be formed between bases on the phosphate backbone of DNA. An example is the formation of pyrimidine dimers upon exposure to the physical agent ultraviolet light. Most chemical agents that react with DNA can also form adducts with proteins; however, the extent of the reaction with each often differs greatly. ALKYLATING AGENT A substance that causes the addition of an alkyl group to an organic compound; according to the number of reactive groups they contain, alkylating agents are classified as monofunctional, bifunctional, or polyfunctional; many alkylating agents are mutagenic to humans. ALKYLATION The addition of alkyl groups, such as methyl or ethyl groups, to another chemical; for example, the mutagen ethyl methanesulfonate (EMS) adds ethyl groups to DNA, forming adducts such as N7-ethylguanine; EMS is said to be an alkylating agent and to alkylate DNA. 79

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SO DRINKING WATER AND HEALTH ANTIGEN A substance capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response. ANTISERUM An antibody-containing serum generated by an animal or human as an immunologic response to infection. 8-AZAGUANINE An analogue of the normal DNA and RNA purine base guanine; selection for resistance to the toxic effects of 8-azaguanine is the basis for several mutation-detection systems. BASELINE ADDUCTS Endogenous adducts found on DNA from "unexposed" organisms or individuals. The source of these adducts is unknown. BINDING Formation of adducts by chemical linkage between an exogenous compound and a normal cellular macromolecule. BIOLOGIC DOSIMETER The use of a cellular molecule that undergoes a change following a reaction with a specific agent or class of agents as an estimate of dose to the target tissue or as a marker of exposure or effect. BIOLOGIC END POINT Target tissue; the site of toxic action. BIOTRANSFORMATION The series of chemical alterations of a compound oc- curring within the body, as by enzymatic activity. CARCINOGEN A chemical or physical agent which causes an increase in tumor rate in exposed organisms or individuals. CENTROMERE A specialized part of a chromosome that attaches to a spindle fiber during cell division. CHROMATID One of the identical longitudinal halves of a chromosome, sharing a common centromere with a sister chromatic; produced by the replication of a chromosome during interphase. (See SISTER-CHROMATID EX- CHANGE) CHROMOSOME A nucleoprotein structure, generally more or less rodlike during nuclear division; a physical structure that bears genes; each species has a characteristic number of chromosomes. CHRONIC ANIMAL BIOASSAY Long-term (90 days to lifetime) exposure study, usually conducted in small rodents (mice and rats), to determine, in the context of this report, the carcinogenicity of a chemical or physical agent.

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Glossary 8 1 CODING SEQUENCE The region of a gene (DNA) that encodes the amino acid sequence of a protein. COVALENT BINDING A stable chemical bond formed between two atoms in which electrons are shared by both. CROSS-LINKING The joining of two DNA strands or a DNA strand with a protein strand by a bifunctional or polyfunctional alkylating agent. An inter- strand cross-link binds two separate strands together; an intrastrand cross- link joins different parts of the same DNA strand. CYTOSINE DEAMINATION The removal of the NH2 group from the C4 atom of cytosine, converting the cytosine to uracil. DNA Deoxyribonucleic acid, the genetic material of every cell. DNA ALTERATIONS Changes in the nucleotide sequence or the structural in- tegrity of the normal DNA molecule of a cell or organism. DNA DAMAGE Any modification of DNA that alters its normal structure, its coding properties, or its normal function in replication or transcription. DNA LESIONS DNA alterations that form the basis of mutation. DEPURINATION The process of removal of a purine base, either guanine or adenine, from DNA. DEPYRIMIDINATION The process of removal of a pyrimidine base, either thy- mine or cytosine, from DNA. DETOXIFICATION The metabolic conversion of a substance into another substance of lower toxicity; the mammalian liver is an important site of detoxification processes. (See also METABOLIC ACTIVATION and TOXIFICATION) DEVELOPMENTAL EFFECTS Embryonic (fetal) growth retardation, malforma- tions, or death produced by exposures during embryonic stages of devel- opment, usually at levels that do not induce severe toxicity in the mother. DIPLOID An organism or cell having two complete sets of chromosomes, with each set typically of a different parental origin. DOMINANT LETHAL MUTATION A mutation of the germ cell that results- in embryonic or fetal death.

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82 DRINKING WATER AND HEALTH DOSE Used loosely as equivalent to quantity or extent of exposure. Specifically, as DOSE TO THE TARGET TISSUE, the amount of material, expressed as time integral of concentration, that reaches a biologically significant target; BIOLOGICALLY EFFECTIVE DOSE, the number of adducts per nucleotide or per unit of protein. DOSIMETRY Scientific determination of amount, rate, and distribution of a dose (chemical or physical) to a particular target. ELECTROPHILE An agent with an affinity for a pair of electrons that bonds with a substance (i.e., with a nucleophile) offering a pair of electrons; because there are many nucleophilic sites in DNA, electrophiles can react with DNA to produce a variety of adducts; many metabolically activated mutagens and carcinogens or their metabolites are electrophilic. ENZYMATIC REPAIR SYSTEMS Cellular enzymes capable of recognizing and repairing altered DNA templates. EXCISION REPAIR The enzymatic removal from DNA of an altered base or nucleotide, followed by resynthesis and rejoining of the DNA. Various different enzymatic pathways for excision repair are recognized. EXOCYCLIC Refers to chemical groups not in the basic ring structures of the bases in DNA. For example, the NH2 group on the C4 atom of cytosine is such a group. EXPOSURE In the context of this report, amount of material ingested, inhaled, or otherwise received by an organism. (See also DOSE) FEMTOMOLE 10- ~5 moles. GENOME A complete set of chromosomes or of chromosomal genes. GENETIC TOXICITY The capacity to cause an adverse effect on a genetic system, including mutagenesis and other indicators of genetic damage. GERM CELL Any cell that will eventually differentiate into a mature sex cell (sperm or oocyte). HAPTEN The portion of an antigenic molecule or complex that determines its immunologic specificity.

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Glossary '33 HAZARD IDENTIFICATION Determination of the potential for an agent to pro- duce toxicity. HEPATOCARCINOGEN A chemical that causes cancer in the liver. HEPATOCELLULAR CARCINOMA A cancer pertaining to or affecting liver cells. HEPATOCYTE A parenchymal liver cell. HERITABILITY The ability to be passed on from one cell generation to another or from one individual to an offspring. HERITABLE TRANSLOCATION A stable rearrangement of the position of chro- mosomal segments that leads to successful chromosomal replication and progeny that carry the translocation. HPRT Hypoxanthine-guanine phosphoribosyl transferase (also called HGPRT); an enzyme involved in the utilization of the purine bases hypoxanthine and guanine in mammalian cells (there are related enzymes in submammalian species; mutants that lack HPRT are resistant to the toxic effects of the guanine analogues 8-azaguanine and 6-thioguanine, which can therefore be used to select HPRT mutants and form the basis of several mutation-detection systems. "HOT SPOT" A DNA site or sequence that is particularly susceptible to the formation of alterations that result in mutations. IMMUNOGEN Any substance capable of eliciting an immune response. INTRAPERITONEAL Referring to the abdominal region within the peritoneum. LOCUS The position that a particular gene occupies in a chromosome. METABOLIC ACTIVATION The metabolic conversion of a promutagen into a mutagen as an aspect of toxification; the possibility that a chemical may undergo toxification in vivo provides the rationale for using S-9 mixtures or other metabolic activation systems with many in vitro genetic toxicity tests. (See also ACTIVATING ENZYME and DETOXIFICATION) METHYLATING AGENT A chemical that can transfer a methyl (CH3) group to another compound.

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84 DRINKING WATER AND HEALTH MISCODING An alteration in DNA that changes the readout of information from the usual amino acid to a different amino acid. MOLECULAR DOSIMETRY The measurement of chemical dose at a particular target organ or tissue by examination of configurational or chemical changes in cellular molecules. MUTAGEN An agent that causes mutation. MUTATION A permanent change in genotype other than one brought about by genetic recombination. NONINVASIVE In reference to analytical techniques requiring a test specimen, not involving injury to the subject. NUCLEOPHILIC SITE Within a chemical structure, a region with a negative charge that attracts positively charged chemical groups, or donates electrons. (See also ELECTROPHILE) NUCLEOTIDE The monomeric unit of polynucleotide polymers known as nu- cleic acids; consists of three components a ribose or a 2-deoxyribose sugar, a pyrimidine or purine base, and a phosphate group each of which exists as a phosphate ester of the N-glycoside of the nitrogenous base. NUCLEOTIDE EXCISION Repair by the enzymatic removal of a nucleotide or oligonucleotide containing an altered base followed by synthesis and re- joining of the DNA. (See EXCISION REPAIR) PHARMACODYNAMIC Pertaining to the biochemical processing and physiologic effects of xenobiotic compounds within a living organism. PHARMACOKINETICS The movement in time of xenobiotic compounds in the body, including the processes of absorption, distribution, localization in tissues, biotransformation, and excretion. PROMOTER A chemical compound that advances the process of carcinogenesis begun by other agents. PROMUTAGEN An agent that can become a mutagen if metabolically activated. PROTAMINE A small, basic protein that is rich in the amino acid argenine and contains a positive charge. In late stages of spermatid maturation, protamines neutralize the negative charges on DNA by replacing the usual uncharged

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Glossary 85 chromosomal proteins (histones) and thus facilitate DNA folding and pack- ag~ng. PURINES Two of the bases found in DNA belong to this chemical class. They are guanine (G) and adenine (A). They are linked to the C1 position of deoxyribose, the sugar found in the DNA backbone. PYRIMIDINE The other two bases in DNA belong to this chemical class. They are cytosine (C) and thymidine (T). They are linked to the C1 position of deoxyribose, the sugar found in the DNA backbone. The usual base pairs in DNA are G-C and A-T. PYRIMIDINE DIMERS Adjacent pyrimidine bases in DNA that are joined by a cyclobutane ring as a result of short wavelength UV irradiation. RADIOLABELING The process of incorporating a radioactive isotope of an atom into a larger chemical structure to produce a marker. RECESSIVE LETHAL MUTATION A gene alteration which, when homozygous, results in a mutant phenotype, but which, when heterozygous, results in a normal or near normal phenotype. REPLICATION In the synthesis of new DNA from preexisting DNA, the for- mation of replicas from a model or template; the process by which genes (hereditary material; DNA) duplicate themselves. RISK ASSESSMENT Includes four components: hazard identification, exposure assessment, dose-response assessment, and characterization of risk at pro- jected levels and patterns of exposure. Qualitative risk assessment involves only the first two, and sometimes a limited amount of the third, whereas quantitative estimates of human risk include all four components and in- volve more uncertainties and less consensus about the most appropriate animal models, data sets, and conversion factors to use in calculation. Nevertheless, there are compelling arguments favoring the use of animal data for quantitative risk assessments. S-9 A metabolic activation mixture (i.e., microsomal and cytosolic enzymes) derived from a mammalian liver homogenate. S-9 is used with many in vitro genetic-toxicity tests to provide for the conversion of promutagens into mutagens. (See also ACTIVATING ENZYME) SENSITIVITY The proportion of test cells or animals that are positive in the

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86 DRINKING WATER AND HEALTH system being evaluated; the capacity of a test to detect small increases in toxic effects. SINGLE-STRAND BREAK A break occurring in the phosphate backbone of one strand of a double-stranded DNA molecule. SISTER-CHROMATID EXCHANGE The exchange of segments between the two chromatics of a chromosome. (See also CHROMATID) SPECIFICITY The quality of affecting only certain organs or tissues, or reacting only with certain substances. SPERMATIDS Immature male germ cells that are nearly fully differentiated as sperm cells. SPERMATAZOA Fully mature sex cells in the male. SPERMIOGENIC Referring to those germ cell stages in the male from meiosis onward, in which spermatids and spermatozoa are differentiating. TEMPLATE In genetics, a strand of DNA that specifies the synthesis of a strand of ribonucleic acid (RNA) complementary to itself or of messenger RNA that in turn serves as a template for the synthesis of proteins. 6-THIOGUANINE An analogue of the purine base guanine, which is a normal component of DNA and RNA; selection for resistance to the toxic effects of 6-thioguanine is the basis of several mutation-detection systems. THYMIDINE KINASE (TK) An enzyme involved in the utilization of the nucleo- tide thymidine (which ultimately becomes part of the structure of DNA); catalyzes the phosphorylation of thymidine to thymidine monophosphate; mutants that lack TK are resistant to the toxic effects of several thymidine analogues, including bromodeoxyuridine and trifluorothymidine; selection of these drug-resistant mutants provides the basis of several mutation-de- tection systems, most notably in mammalian cells. TIME-WEIGHTED AVERAGE An average exposure concentration calculated from intermittent samplings of exposure concentrations. TOXICANT Any substance that, through its chemical action, causes adverse effects in living organisms. TOXIFICATION The metabolic conversion of a substance into another substance

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Glossary 87 that has greater toxicity; sometimes occurs as a consequence of processes that are usually associated with detoxification. (See also METABOLIC ACTIVATION) TRANSCRIPTION The synthesis of RNA on a DNA template in such a way that the sequence of nucleotides in the RNA is the complement of the sequence of nucleotides in DNA. VALIDATION The process by which the consistency of a particular test is de- termined; the concordance of results of a test in question and previously established tests for a representative sample of chemicals is evaluated. XENOBIOTIC Originating outside or caused by factors outside the organism; pertaining to that which is not a normal physiologic part of an organism.

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