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TOOLS OF RISK ANALYSIS Applications of Epidemiology I. Overview II. Risk assessment epidemiology A. Definition: a description of the change in the incidence rate of a disease due to a known change in the level of exposure to a cause B. Purposes: - guide public health policies - guide the regulatory process __~ assist in tort resolution C. Foundations • - basic science - ~Q~e ~ ~~~e~ ~ - animal studies `dcseribe eney D. Growing importance of epidemiology : - 0-5u-3~3 tkie- ~-'advances in methodology a tj~-F IcLat. !~ reduced reliance on animal research CSF~_c~ts oaU~~~ bases in law ~'nlmciCs hcwe c~ stnc~ l~ expo:~~ o rx~ ~hC_ destre_ ~~rc&~ e. o rz oS{'ec"E- III. Epidemiology - general A. Definitions: the study of the distribution and determinants of disease in man an observational science dealing with the environmental causes of diseases of human beings B. Strengths - human beings - human lifestyles C. Limitations - non-experimental - often qualitative IV. Selected measures A. Incidence rate I = new cases/(population x time) ~ example: the incidence rate of leukemia is ~ i k 10.1 cases per 100,000 person-years N ~ B. R s R = new cases/population C11 L example: the lifetime risk of developing leukemia is 700 per 100,000 * lk C11 ~ persons, or 0.7% ~ ;A

2 C. Relative incidence rate (relative risk, RR) R?q= the incidence rate in an exposed group divided by that in a non-exposed group example: the RI of leukemia among rubber workers is 4.5 (base = 1.0) D. Standardized mortality ratio SMR = the number of deaths observed (usually in an occupational group) divided by the number of deaths expected example: among pliofilm workers the SMR is 337 (base = 100) V. Study designs - general A. Descriptive studies aF, `1~ »cl~vrcluc~ ~'~0c`~ ~ejn-c~ u s~ud~~ C~rrela E~,~Q 5~~d~es o_qroucto 1.3 B. Follow-up (cohort) studies a. prospective is b. retrospective + C. Case-control- lcss «,j2,,4,,+ ~~- R A- s elec~n- °-6 \DXI,tr) w;-~h PeePz, wO"rt ar'd wi1'hoLd' drstLLse 14 de1ermrne exFb2U'u_ D. Proportional mortality ratio (PMR) VI. Study designs - specific Limitations: A. The retrospective follow-up design Example: 1165 rubber hydrochloride (pliofilm) workers followed-up from 1950-81 experi- enced 9 deaths from leukemia with 2.7 expected, an SMR of 337 Advantages: fast, inexpensive (- -0 exposure based profile of effects (all causes of death) relatively free of bias ( s'{6ic,omct~l~ cc-rcr~ inadequate exposure-possible (jn~a inadequate exposure documentation - usual ~ prone to chance•- 0 prone to confounding N C11

- 3 - B. The case-control design 0~'fcr) ct6cd -A- R14 ~ o~ ~f s r~ ereal -a) 0 J- (J ~i cJ }~reer s~ Example: 138 adults with leukemia, resident in Olmsted County M, were compared with 276 adults without leukemia. Informa- tion on benzene exposure was abstracted from medical records. Among persons with benzene exposure, the RI of leuke- mia was 3.3 compared to persons without exposure. Advantages : fast 6 s profile of exposures control confounding precise (not prone to chance) suitable for rare disease Limitations: single disease only relative measures cp juests ~ prone to bias -c/rffrc.c,~ -1-o fi)+-ove-. 7"h-G2?Le 4'u~ 'Ae sa me 2s ~, e, ~cs VI I. Interpretations -4-0-w Ck0_t)Vf_5f_ I~lu e r~e ~ oczf ~e~rn ~ A. Chance B. Bias d ~s~ c~n ~hc~~e i u C. Confounding - D. Valid d 1seQ.,SeS causal null Comment: not mutually exclusive not permanent VIII. Causality A. Individual study strength internal consistency biological credibility B. Abstract, general case external consistency response to manipulation

- 4 - C. Specific individual case - ~or CC.-ses relevant exposure absence of alternative cause IX. Benzene and leukemia - A model risk assessment A. Basic science not genotoxic n 'c- damages chromosomes -~nv'- ciec- hcd ~-nec i anlsy~ B. Animal studies carcinogenic leukemogenicity problematic 14 p~ C. Epidemiologic studies l'7 s1;eg ~~~\,generally positive for AML -r\ecc-~,Ue~ S~~zs ~G; ~poor quantification of exposure some potential confounding - o{-t,,r so1,;{rrt D. Epidemiologic data* - observed deaths : CL 19 - expected deaths: 9.6 - total deaths: 1273 - mean cum. exposure: 42 ppm-yrs E. Risk assessment - excess deaths: 19-9.6 = 9.4 - excess deaths/1000: 9. 4/1 .273 = 7. 4/1000 -~~1'~'~~ - baseline risk: 7/1000 - doubling dose: - ~ (14/14.7)(42 ppm-yrs) = 40 ppm-yrs ~'rn c~es ~ ,~eed ~ be cxposed 4-0 do«b!e AhL P ts iC X. The OSHA standard ~~G Pp-ft.U A. For many years = 10 ppm 8 hr TWA 30 yrs x 10 ppm = 300 ppm-yrs ti 7 doublings = 800/1000 = unacceptable 1.7 additions ti 56 deaths/1000 B. Currently =IL ppm 8 hr TWA '3 ` 30 ppm yrs ti 1.75 baseline ti 5 excess deaths/1000 exposed

- 5 - C. Issues - _A'lodel CissLCmes - - linear dose response - non-threshold - other 4 September 1991 Philip Cole, M.D. Austin H, Delzell E, Cole P: Benzene and leukemia: A review of thE: literature and a risk assessment. Am J Epidemiol 127: 419-439, 1988.