Appendixes



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Scientific Frontiers in Developmental Toxicology and Risk Assessment Appendixes

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Appendix A Glossary Acceptable daily intake (ADI) An estimate of the daily exposure dose that is likely to be without deleterious effect even if continued exposure occurs over a lifetime. A/D ratio The ratio of the adult toxic dose to the developmentally toxic dose. Allele A gene’s representation on one chromosome. Benchmark dose (BMD) An alternative approach to the NOAEL approach that uses all experimental data to fit one or more dose-response curves. Bioinformatics The study of how to most efficiently manage and utilize vast amounts of genomic sequence data. Biological markers (biomarkers) Indicators signaling events in biological systems or samples (NRC 1989). There are three classes of biomarkers—exposure, effect, and susceptibility. A marker of exposure is an exogenous substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target molecule or cell that is measured in a compartment within an organism. A marker of effect is a measurable biochemical, physiological, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease. A marker of susceptibility is an indicator of an

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Scientific Frontiers in Developmental Toxicology and Risk Assessment inherent or acquired limitation of an organism’s ability to respond to the challenge of exposure to a specific xenobiotic substance. Checkpoint pathway Type of pathway used in intracellular signaling. Checkpoint pathways are induced in response to a cell’s own internal imbalance or errors in its synthetic activities. Induction of checkpoint pathways leads to a delay in certain synthetic processes until other processes are complete, thereby averting damage. Chimera An animal consisting of genetically different cells derived from two (or more) different zygotes. Chromosomes Structures that contain an organism’s genes. Cleavage The first few divisions of an embryo following fertilization. There is little or no growth during these divisions and the cytoplasm is cleaved into smaller and smaller units. Complementary DNA (cDNA) DNA copy of mRNA from expressed genes made by the enzyme reverse transcriptase. Cre/loxP Bacterial recombinase system in which the Cre protein mediates DNA recombination between specific DNA sequences known as lox-P sites. This system is used in mammalian cells to delete (or invert) a stretch of DNA by flanking it with lox-P sites and then exposing the cell to Cre protein at some predetermined time. Deoxyribonucleic acid (DNA) A complex macromolecule that is composed of nucleic acids (adenine, guanine, cytosine, and thymine) and is found in cellular organisms. DNA carries all the genetic information necessary to determine the specific properties of an organism. In its native state, DNA exists as a double helix. Developmental defect A structural or functional anomaly that results from an alteration in normal development. Developmental toxicant A physical, chemical, or biological agent that is shown to affect development under specific conditions of exposure.

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Developmental toxicology The study of adverse effects on the developing organism that might result from exposure prior to conception (of either parent), during prenatal development, or from postnatal development to the time of sexual maturation. Developmental biology The study of the biology of normal development. Developmental susceptibility gene Any gene that encodes a gene product with which an environmental agent can interfere and cause a perturbation of normal development. Drug metabolizing enzyme (DME) Enzymes that metabolize endogenous substrates and also foreign chemicals. Among individuals, there are heritable differences in the catalytic activity of DMEs and in the ability to produce high levels of DMEs. Ecogenetics The study of the inherited basis of individuals’ different responses to environmental agents. Ectopic expression Expression of a gene in a tissue in which it is not normally expressed. Electroporation A means of introducing molecules into cells by transiently permeabilizing their membranes with a brief electric shock. Embryonic stem (ES) cells Permanent in vitro stem-cell lines derived from the undifferentiated cells of a very early, preimplantation mammalian embryo. They have the potential to contribute to all cells of a developing embryo when they are placed into an early embryonic environment. Environmental factor Physical, chemical, and biological agents or conditions encountered by humans, such as infections, nutritional deficiencies and excesses, life-style factors (e.g., alcohol), hyperthermia, ultraviolet radiation, X-rays, and the myriad of manufactured chemicals (e.g., pharmaceuticals, synthetic chemicals, solvents, pesticides, fungicides, herbicides, cosmetics, and food additives) and natural materials (e.g., plant and animal toxins and products). Epistasis A situation in which the phenotypic expression of one gene obscures the phenotypic effects of another gene. Eukaryotic Cells in which the genetic material is separated from the cytoplasm by a nuclear membrane.

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Exon Nucleotide segment that codes for amino acids. Expressed sequence tag (EST) A DNA sequence complementary to a known piece of transcribed RNA. Forward genetics An approach to identify a particular gene starting with some knowledge about a mutant phenotype. Functional genomics The systematic and comprehensive analysis of gene products, including mRNAs and proteins. Gene The fundamental units of heredity carried by DNA. Gene product The mRNA resulting from transcription of a gene and the protein translated from the mRNA. Gene targeting The production of a mutation in a specific “target” gene using molecular biological techniques. Genomics The study of the genetic composition of organisms. Genotype An organism’s genetic makeup (i.e., its DNA sequence). Homeobox A region of the homeotic genes that is highly conserved among several species, including Drosophila, frogs, and mammals. The homeobox sequence encodes a DNA-binding motif of the encoded protein that is a transcription factor. Homologous recombination Crossing over between two identical or homologous strands of DNA. Human Genome Project A federally funded initiative to sequence and identify (HGP) all human genes. HGP also involves studying the genome of a number of organisms other than humans, including insects, fish, plants, and other mammals. Inbred strain A strain of mice that has been inbred by brother-sister matings for more than 20 generations, and consequently all the individuals of the strain are more than 98% genetically identical. Intron DNA sequence between exons that is transcribed but not translated Knockout mutation A mutation that leads to the loss of function of a particular gene. Also called a null mutation.

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Linkage disequilibrium The condition in which two genes are close enough together on a chromosome that it is not likely that they will be separated by recombination during meiosis. Linkage analysis A means of statistically correlating phenotype with genotype using lod scores. Lod score The ratio of the likelihood of two or more loci remaining together when chromosomes recombine (true linkage) to the likelihood of chance alone. Lowest-observed-adverse-effect level (LOAEL) The lowest exposure level at which there are statistically or biologically significant increases in the frequency or severity of adverse effects in the exposed population and its appropriate control. Margin of exposure (MOE) The ratio of the NOAEL to the estimated exposure dose. Maximum tolerated dose (MTD) The maximum dose that an animal species can tolerate for a major portion of its lifetime without significant impairment or toxic effect other than carcinogenicity. Mechanism of action The detailed molecular knowledge of the events that result in an adverse developmental response in an organism. This knowledge includes the following types of mechanistic information: (1) The toxicant’s kinetics and means of absorption, distribution, metabolism, and excretion within the mother and conceptus; (2) Its interaction (or those of a metabolite derived from it) with specific molecular components of cellular or developmental processes in the conceptus or with maternal or extraembryonic components of processes supporting development; (3) The consequences of the interactions on the function of the components in a cellular or developmental process; (4) The consequences of the altered process on a developmental outcome, namely, the generation of a defect. See also ‘mode of action.’ Mendelian trait Phenotype that shows simple pattern of inheritance. Mendelian traits are usually governed by a single genetic locus. Mendelian gene A gene located in a chromosome that obeys the laws of Mendelian inheritance.

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Messenger RNA (mRNA) RNA that is derived from transcription of expressed genes. Microsatellites A subclass of minisatellites in which the repeat unit consists of two base pairs (dinucleotide repeats). Minisatellites A class of restriction fragment length polymorphisms in which the restriction fragment length is caused by a variable number of tandem repeats (VNTRs). Mode of action The cascade of events that occurs during the development of a major adverse event, following maternal exposure to a toxicant. See also ‘mechanism of action.’ The description of mode of action contains less molecular information on components, interactions, and processes than does the mechanism of action of a toxicant. Molecular epidemiology The study of correlating genotype with phenotype in human population studies or family studies. Multifactorial inheritance The interaction between allelic variants of genes and environmental conditions in the production of disease. Mutation One or more altered bases in a nucleic acid sequence. No-observed-adverse-effect level (NOAEL) An exposure level at which there are no statistically or biologically significant increases in the frequency or severity of adverse effects between the exposed population and its appropriate control. Some effects may be observed at this level, but they are not considered adverse, nor precursors to adverse effects. Open reading frame (ORF) A sequence that codes for amino acids without any termination codons and is potentially translatable into protein. Organogenesis The organ-forming phase of embryonic development. Phage display A method that enables the presentation of large peptide and protein libraries on the surface of phage particles from which molecules of desired functional property(ies) can be rapidly selected. Pharmacogenetics The study of the heredity basis of differences in response among individuals to pharmacologic drugs. Phenotype A biological trait (e.g., eye color).

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Pleiotropic A gene having multiple phenotypic traits Polymorphism The presence of two or more alleles of a particular gene within a population of organisms. Prokaryotic Cells in which the nuclear region is not separated from the cytoplasm by a membrane. Pronucleus A haploid nucleus formed by either the sperm head or the egg nucleus after fertilization but before the nuclei fuse to form the diploid zygotic nucleus. Proteomics Analysis of an organism’s protein composition and function. Reference dose (RfD) An estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Reference concentration (RfC) An estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious noncancer effects during a lifetime. Relative risk The ratio of incidence or risk among exposed individuals to incidence or risk among nonexposed individuals. Restriction fragment length polymorphism (RFLP) Variations in DNA sequence that are indicated by the presence or absence of particular restriction sites in the DNA. Restriction sites Specific, short DNA sequences that are recognized by restriction enzymes that cleave the duplex DNA. Reverse genetics An approach to identify the function of a particular gene starting with a cloned copy of that gene. Ribonucleic acid (RNA) A complex macromolecule composed of adenine, cytosine, guanine, and uracil that is found in cellular organisms. RNA can serve several functions, including encoding the genetic information copied from DNA in the form of a sequence of bases that specifies a sequence of amino acids.

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Risk assessment The evaluation of scientific information on the hazardous properties of environmental agents and on the extent of human exposure to those agents. The product of the evaluation is a statement regarding the probability that populations (expressed qualitatively or quantitatively) so exposed will be harmed and to what degree. Risk characterization The integration of both qualitative and quantitative information from hazard identification and assessment of exposure and dose-response relationships. It is usually the last step in the risk assessment process and it includes an evaluation of uncertainty and variability in the assessment that would significantly influence the analysis. RNAi Inactivation of a gene by the introduction into cells of double-stranded mRNA for that gene. Saturation mutagenesis Mutagenesis screen in which enough mutants are produced to obtain all the different kinds of mutants affecting a particular process. Selector genes Genes that encode transcription factors. Transcription factors “select” which other genes will be expressed. Sensitized strain A model organism that contains a mutated pathway (e.g., signal transduction pathway), but the mutation causes no visible phenotype. The mutated pathway is close to a threshold of function and sensitive to an otherwise asymptomatic change in activity of a second element in the pathway. Signal transduction pathway Type of pathway used for cell-to-cell (intercellular) signaling. Signal transduction pathways can have from 1 to 10 intermediates. These pathways are used extensively during development. Single nucleotide repeat (SNP) A variation between individuals in one base pair at a specific location of a DNA sequence. Spemann organizer A group of cells that releases inducer proteins that are important in the placement, orientation, and scaling of later development by surrounding cells.

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Scientific Frontiers in Developmental Toxicology and Risk Assessment Stress pathway Type of pathway used in intracellular signaling. Stress pathways are induced when a disruption of normal cell function and development occurs due to physical or chemical agents of the environment. Induction of stress pathways leads to cellular repair and counteraction. Toxicity The process by which a toxicant enters an organism, how it reacts with target molecules, how it exerts its deleterious effects, and how the organism reacts to the insult. Toxicodynamics The study of how a toxic chemical (or metabolites derived from it) interacts with specific molecular components of cellular and, in the context of this report, developmental processes in the body. Toxicokinetics The study of how a toxic chemical is absorbed, distributed, metabolized, and excreted into and from the body. Transcription factor A DNA binding protein that is involved in the formation of mRNA. Transgenic Any animal whose genome has been altered by addition of genetic material or by alteration of existing genes by gene targeting. Uncertainty factor (UF) One of several factors used in calculating an exposure level that will not cause toxicity from experimental data. UFs are used to account for the variation in susceptibility among humans, the uncertainty in extrapolating from experimental animal data to humans, the uncertainty in extrapolating from data from studies in which agents are given for less than a lifetime, and the uncertainty in using LOAEL data instead of NOAEL data. Wild type The normal or usual allele or phenotype. In cases in which multiple allelic variants have a normal phenotype, the wild-type allele is usually considered the most common one. Zygote An embryo newly formed as a result of fertilization.