Genetics, Testing and Toxic Torts

Genetics Testing and Toxic TortsGenetics, Testing and Toxic Torts

A Presentation to:

ABA

Howard M. Sandler, M.D.Sandler Occupational Medicine Associates, Inc.p

April 2008

© 2009 Sandler Occupational Medicine Associates, Inc.




Common Genetic DisordersDisorder Mutation Chromosome

22q11.2 deletion syndrome D 22q

Angelman syndrome DCP 15

Canavan disease 17p

Celiac disease

Charcot-Marie-Tooth disease Poo Disease

Color blindness P XColor 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 17q/22q/?Neurofibromatosis 17q/22q/?

Phenylketonuria P 12q

Prader-Willi syndrome DC 15

Sickle-cell disease P 11p


Tay-Sachs disease P 15

Turner Syndrome C X

Four Types of Genetic DiseasesFour Types of Genetic Diseases

• Single Gene – CF Sickle Cell AnemiaSingle Gene CF, Sickle Cell Anemia, Hemochromatosis

• Multifunctional (complex or polygenic)• Multifunctional (complex or polygenic) –AD, arthritis, HBP, obesity, cancerCh l D ’ S d• Chromosomal – Down’s Syndrome

• Mitochondrial (relatively rare)


“Cytogenetics”Cytogenetics

• What is Cytogenetics?What is Cytogenetics?• What are Cytogenetic “Markers” and are they

useful in Occupational and Environmental pHealth Evaluation?

• Cytogenetics and Exposure Specificityy g p p y• Cytogenetics and the Carcinogenesis

“Cascade” • Cytogenetics and Risk of Disease


Symbols Used in Chromosome N l tNomenclature

Symbol Definition

A-G Chromosome groups

1-22 Autosome numbers

X,Y Sex chromosomes

/ Diagonal line separating cell lines in descriptions of mosaicismdescriptions of mosaicism

? Identification of chromosome or chromosome structure questionable

+ When placed before the chromosome+ - 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

Symbols Used in Chromosome N l tNomenclature (cont’d)

Symbol Definition

: Break with no reunion

:: Break with reunion

F tFrom…to…

ace Acentric

cen Centromere

del Deletion

der Derivative chromosome

dic Dicentric

dup Duplication



Symbol Definition

end Endoreduplication

h Secondary constriction or negatively staining regionstaining region

i Isochromosome

ins Insertion

inv Inversion

inv ins Inverted insertion

mar Marker chromosomemar Marker chromosome

mat Maternal origin

p Short arm



Symbol Definition

pat Paternal origin

q Long arm

Ri hr Ring chromosome

rep Reciprocal translocation

rec Recombinant chromosome

rob Robertsonian translocation

s Satellite

t Translocation

ter Terminal


Typical Cytogenetic EndpointsTypical Cytogenetic Endpoints

• Peripheral Blood LymphotcytesPeripheral Blood Lymphotcytes• Chromosomal Aberrations (CA)

Si t Ch tid E h (SCE)• Sister Chromatid Exchange (SCE)• Micronuclei• Others – Premature Chromosome

Condensation





Selected Cytogenetics – Benzene StudiesStudies

Cancer predicti e al e of c togenetic• Cancer predictive value of cytogenetic markers used in occupational health surveillance programs: a report from ansurveillance programs: a report from an ongoing study by the European Study Group on Cytogenetic Biomarkers and Health -y gChagmar et al, 1998

• Cytogenetic Changes in Subjects Occupationally Exposed to Benzene – Kasuba et al, 2000


Selected Cytogenetics – Benzene St diStudies (cont’d)

• Utility of a Routine Medical SurveillanceUtility 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


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 inNo Direct Benzene Correlation Between Changes in

Lymphocytes and BMC’s• Increased Cytogenetic Changes are Common• MMS• MMS

– Blood Cell Counts (OSHA)– Blood Cell Indices– Cytogenetics BiomarkersCytogenetics Biomarkers

• No Longitudinal Studies Showing Cytogenetic Changes Specific to Benzene are Correlated with Increased Risk of Disease


Increased Risk of Disease

Cytogenetic Biomarkers/"Genetic Damage” and PositiveDamage and Positive

Associations/Case Reports• Ageg• Medication – e.g., Thimerosal• Smoking, Alcohol, other Personal Risk Factorsg, ,• Ionizing Radiation• Illnesses• Occupational and Environmental Factors

– Air PollutionLead– Lead

– Methotrexate– Noise and Vibration

Vincristine


– Vincristine

Trisomy 8 and Trisomy 22 in B E d W kBenzene-Exposed Workers

• “Selective effects were… observed on trisomy yinduction with chromosomes 8, 21 and 22 having the highest IRRs [Incidence Rate Ratios] (IRR > 3, p < 0.005).”] ( , p )

• Zhang, L., et al., “Application of an O t Ch FISH d i t d t t l k iOctoChrome FISH device to detect leukemia and lymphoma specific chromosome aberrations in molecular epidemiology and

i l ” Ab N 3810 dtoxicology,” Abstract No. 3810 presented at the 2002 Annual Meeting of the American Association for Cancer Research


Cytogenetic Testing – Ready for L l P i ti ?Legal Primetime?

• Markers for what?Markers for what?– Exposure level and source

Timing of exposure– Timing of exposure– General causation

Individual causation– Individual causation• How long do cytogenetic markers last?


Cytogenetic Testing – Ready for L l P i ti ?Legal Primetime? (cont’d)

• What do you do with multiple, non-What do you do with multiple, nonspecific markers?

• Marker-disease specificity (eg, allMarker disease specificity (eg, all hemopioetic cancers?)

• Smith v. GillisSmith v. Gillis– Cytokine Institute claims– Multiple chemicalsu t p e c e ca s– Multiple diseases– Effect timing


g

Thank You For Your InterestThank You For Your Interest

“ Celebrating 25 Years…We invite you to visit our website at www.somaonline.com”

Presented previously by Lisa Kalman,PhD


Documents

Genetics, Testing and Toxic Torts