A Presentation to: ABA. Howard M. Sandler, M.D. Sandler Occupational Medicine Associates, Inc. April 2008
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1 Genetics, Testing and Toxic Torts A Presentation to: ABA Howard M. Sandler, M.D. Sandler Occupational Medicine Associates, Inc. April 2008
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6 Common Genetic Disorders Disorder Mutation Chromosome 22q11.2 deletion syndrome D 22q Angelman syndrome DCP 15 Canavan disease 17p Celiac disease Charcot-Marie-Tooth disease Color blindness P X Cri du chat D 5 Cystic fibrosis P 7p Down syndrome C 21 Duchenne muscular dystrophy D Xp Haemophilia P X Klinefelter syndrome C X Neurofibromatosis Phenylketonuria P 12q Prader-Willi syndrome DC 15 Sickle-cell disease P 11p Tay-Sachs disease P 15 Turner Syndrome C X Poo Disease 17q/22q/?
7 Four Types of Genetic Diseases Single Gene CF, Sickle Cell Anemia, Hemochromatosis Multifunctional (complex or polygenic) AD, arthritis, HBP, obesity, cancer Chromosomal Down s Syndrome Mitochondrial (relatively rare)
8 Cytogenetics What is Cytogenetics? What are Cytogenetic Markers and are they useful in Occupational and Environmental Health Evaluation? Cytogenetics and Exposure Specificity Cytogenetics and the Carcinogenesis Cascade Cytogenetics and Risk of Disease
9 Symbols Used in Chromosome Nomenclature Symbol A-G Definition Chromosome groups 1-22 Autosome numbers X,Y Sex chromosomes / Diagonal line separating cell lines in descriptions of mosaicism? Identification of chromosome or chromosome structure questionable + - When placed before the chromosome number, these denote additional of loss of a whole chromosome; when placed after the chromosome number, they denote an increase or decrease in length of a chromosome part
10 Symbols Used in Chromosome Nomenclature (cont d) Symbol Definition : Break with no reunion :: Break with reunion From to ace cen del der dic dup Acentric Centromere Deletion Derivative chromosome Dicentric Duplication
11 Symbols Used in Chromosome Nomenclature (cont d) Symbol end h i ins inv inv ins mar mat p Endoreduplication Definition Secondary constriction or negatively staining region Isochromosome Insertion Inversion Inverted insertion Marker chromosome Maternal origin Short arm
12 Symbols Used in Chromosome Nomenclature (cont d) Symbol pat q r rep rec rob s t ter Definition Paternal origin Long arm Ring chromosome Reciprocal translocation Recombinant chromosome Robertsonian translocation Satellite Translocation Terminal
13 Typical Cytogenetic Endpoints Peripheral Blood Lymphotcytes Chromosomal Aberrations (CA) Sister Chromatid Exchange (SCE) Micronuclei Others Premature Chromosome Condensation
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17 Selected Cytogenetics Benzene Studies Cancer predictive e value of cytogenetic markers used in occupational health surveillance programs: a report from an ongoing study by the European Study Group on Cytogenetic Biomarkers and Health - Chagmar et al, 1998 Cytogenetic Changes in Subjects Occupationally Exposed to Benzene Kasuba et al, 2000
18 Selected Cytogenetics Benzene Studies (cont d) Utility of a Routine Medical Surveillance Program with Benzene Exposed Workers Bogadi-Sare et al, 2003 Evaluation of Lymphopenia Among Workers with Low-Level Benzene Exposure and the Utility of Routine Data Collection - Collins et al, 1997
19 Cytogenetics and Benzene State of the Art Benzene Exposure Produces Changes in Lymphocytes and Bone Marrow Cells at High Exposure Levels (>50 ppm) Small Studies, Issues of Confounding Data is Inconsistent in Studies at Lower Levels No Direct Benzene Correlation Between Changes in Lymphocytes and BMC s Increased Cytogenetic Changes are Common MMS Blood Cell Counts (OSHA) Blood Cell Indices Cytogenetics Biomarkers No Longitudinal Studies Showing Cytogenetic Changes Specific to Benzene are Correlated with Increased Risk of Disease
20 Cytogenetic Biomarkers/"Genetic Damage and Positive Associations/Case Reports Age Medication e.g., Thimerosal Smoking, Alcohol, other Personal Risk Factors Ionizing Radiation Illnesses Occupational and Environmental Factors Air Pollution Lead Methotrexate Noise and Vibration Vincristine
21 Trisomy 8 and Trisomy 22 in Benzene-Exposed Workers Selective effects were observed on trisomy induction with chromosomes 8, 21 and 22 having the highest IRRs [Incidence Rate Ratios] ](IRR > 3,,p < 0.005). Zhang, L., et al., Application of an OctoChrome FISH device to detect t leukemia and lymphoma specific chromosome aberrations in molecular epidemiology and toxicology, Abstract No presented at the 2002 Annual Meeting of the American Association for Cancer Research
22 Cytogenetic Testing Ready for Markers for what? Legal Primetime? Exposure level and source Timing of exposure General causation Individual causation How long do cytogenetic markers last?
23 Cytogenetic Testing Ready for Legal Primetime? (cont d) What do you do with multiple, non- specific markers? Marker-disease specificity (eg, all hemopioetic cancers?) Smith v. Gillis Cytokine Institute claims Multiple utpechemicals cas Multiple diseases Effect timing
24 Thank You For Your Interest Celebrating 25 Years We invite you to visit our website at Presented previously by Lisa Kalman,PhD
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