Observations on the dose-response curve for arsenic exposure and lung cancer
Hertz-Picciotto I, Smith AH.
Scand J Work Environ Health, 1993 Aug;19(4):217-26.

Information from published studies concerning arsenic inhalation and lung cancer risks was analyzed. It was found that all of the studies with quantitative data were consistent with a supralinear dose-response relationship. Various factors which might be distorting the true biological dose-response were assessed. These included the fact that the workers thought to be most highly exposed might actually have had lower exposures than reviously quantified by air sampling as a result of non-random sampling and the possible use of respirators when air levels were highest. It was noted that there was a linear dose-response relationship in one study, which used urine arsenic measurements to assess exposure.

 

Human studies do not support the methylation threshold hypothesis for the toxicity of inorganic arsenic
Hopenhayn-Rich C, Smith AH, Goeden H.
Environ Res, 60: 161-77, 1993.

The validity of the methylation threshold hypothesis was examined on the basis of published studies. The results indicated that epidemiological and experimental human data does not support the inorganic arsenic methylation threshold hypothesis. Regardless of the absorbed dose of inorganic arsenic, there was always some unmethylated inorganic arsenic present in the urine, even at background exposure levels. It was noted that lack of evidence for a methylation threshold based on the human exposure levels studied did not exclude the possibility of other threshold mechanisms. In addition, the considerable variation in methylation of inorganic arsenic observed between individuals was noted to warrant further study.

 

Confidence limit analyses should replace power calculations in the interpretation of epidemiologic studies
Smith AH, Bates MN.
Epidemiology, 1992 Sep;3(5):449-52.

Frequently, after an epidemiologic study is completed, statistical power to detect a relative risk of interest is recalculated using data obtained during the course of the study. A negative study may then be dismissed on the grounds that its power was too low. However, post hoc power calculations ignore the actual relative estimate and its variance, which are by then known. We present evidence that post-study power calculations have little value and should be replaced by a more informative method using the upper (1 - alpha)% confidence limit of the point estimate that touches the value of the relative risk of interest.

 

Synergism between occupational arsenic exposure and smoking in the induction of lung cancer
Hertz-Picciotto I, Smith AH, Holzman D, Lipsett M, Alexeef G.
Epidemiology, 1992 Jan;3(1):23-31.

We assembled data from numerous studies to examine whether active smoking and occupational exposure to arsenic act synergistically (more than additively) to increase the risk of lung cancer. Although several smaller studies lacked the power to reject simple additive relations, the joint effect from both exposures consistently exceeded the sum of the separate effects by about 70 to 130%. The only study not showing a greater than additive effect appeared to have inadequate data to address this question. We calculated the excess fractions for the synergism; these showed that a minimum of between 30% and 54% of lung cancer cases among those with both exposures could not be attributed to either one or the other exposure alone. Previous authors addressing the synergism between arsenic exposure and smoking have evaluated deviations from a multiplicative model, which is inappropriate for this purpose. Reports of no interaction or "negative" interaction have therefore been misleading. Taken as a whole, the evidence is compelling that arsenic and smoking act in a synergistic manner to produce lung cancer. Substantial reductions in the lung cancer burden of smokers occupationally exposed to arsenic could be achieved by reductions in either exposure. The mechanism for the synergism is unclear.

 

Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels of New Zealand pesticide applicators and their implication for cancer hypotheses
Smith AH, Patterson DG, Jr., Warner ML, MacKenzie R, Needham LL.
J Natl Cancer Inst, 1992 Jan 15;84(2):104-8.

BACKGROUND: The phenoxyherbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) has been widely used by professional pesticide applicators in New Zealand since before 1950. Epidemiologic studies of the risk of cancer and birth defects have been conducted in this group of workers, but little is known about the extent of their exposure to the 2,4,5-T contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent carcinogen in animals.

PURPOSE: The objective of this study was to determine whether the blood serum levels of TCDD in a group of professional 2,4,5-T applicators in New Zealand were greater than those of a matched control group not involved in 2,4,5-T spraying. METHODS: Of 548 men employed as professional pesticide applicators in New Zealand from 1979 through 1982, nine were selected who had sprayed pesticides, although not necessarily 2,4,5-T, for at least 180 months. These applicators had sprayed 2,4,5-T for a range of 83-372 months. We measured the blood serum levels of polychlorinated dibenzo-p-dioxins and dibenzofurans, which were substituted with chlorine at the 2,3,7,8 position, in the nine pesticide applicators and in a matched group of nine control subjects.

RESULTS: The average serum level of TCDD for applicators was almost 10 times that for the matched control subjects, while the average levels of all other congeners and isomers measured in the two groups did not differ substantially. TCDD levels in eight of the nine applicators were higher than those in the control subjects (mean difference, 47.7 parts per trilion). The variation in TCDD levels among the applicators was related to their duration of work exposure to 2,4,5-T.

CONCLUSIONS: On the basis of our findings in these subjects in New Zealand, we conclude that increased risks of cancer from brief exposure to phenoxyherbicides reported in other countries are probably not attributable to the TCDD that contaminates 2,4,5-T. We cannot determine from these results, however, whether TCDD exposure from prolonged use of 2,4,5-T poses significant health risks.

 

Serum beta-carotene in persons with cancer and their immediate families
Smith AH, Waller KD
Am J Epidemiol, 1991 Apr 1;133(7):661-71.

Inorganic arsenic is known to cause skin cancer by ingestion and lung cancer by inhalation. However, whether arsenic ingestion causes internal cancers is still a matter of debate. This paper has reviewed the epidemiologic literature that bears on this question. Published studies of populations who have ingested arsenic in medicines, wine substitutes, or water supplies, as well as workers exposed to arsenic by inhalation, were considered in terms of whether the observed associations might be explained by the presence of biases, the consistency of the evidence, and the biologic plausibility of the associations. Many studies were found to be uninformative because of low statistical power or potential biases. The most informative studies, which were from Taiwan and Japan, involved exposure to arsenic in drinking water. These studies strongly suggest that ingested inorganic arsenic does cause cancers of the bladder, kidney, lung, and liver, and possibly other sites. However, confirmatory studies are needed.

 

 

Health risk assessment of incinerator air emissions incorporating background ambient air data
Smith AH, Goeden H
Combust Sci Tech, 1990 74:51-61

Combustion of hazardous municipal waste produces a wide variety of emissions which need to be considered when assessing potential human health risks. A major focus in recent years has been excess cancer risks. The main emissions which rodent studies indicate may be carcinogenic to humans include organic chemicals such as dioxins, furans and polychlorinated biphenyls, which are highly persistent in the environment. Certain metals known to be carcinogenic to humans, such as arsenic, cadmium, chromium, and nickel, are also emitted. Priorities for considerations among non-carcinogenic emissions include lead and mercury. Methods for health risk assessment of air emissions are presented in this paper, and illustrated with data from a risk assessment of emissions from municipal waste incinerator. The most significant potential exposure pathways were fish, meat, and milk consumption, which are dependent on the sitting of faciites in relation to fishable lakes and land use for animal grazing or food production. Estimated ground level air concentrations of emissions and an analysis of data concerning background air demonstarte that well-designed incinerators equipped with modern pollution control devices should only make a small contribution to already existing air levels of carcinogenic and non-carcinogenic substances in urban and suburban settings. It is proposed that comparisons of exposure to particular sources of environmental contamination with background exposure to the same substances is critical to effective allocation of resources dealing with environmental pollutants.

 

Epidemiological evidence indicates asbestos causes laryngeal cancer
Smith AH, Handley MA, Wood R
J Occup Med, 1990 Jun;32(6):499-507.

A number of studies have suggested a small to moderate positive relation between blood pressure and blood lead concentration in males (2-4 mmHg/In(microgram/dl]. However, this 1986 study of San Francisco bus drivers suggests larger relations in black males (n = 132) for both systolic pressure (7.5 mmHg/In(microgram/dl] and diastolic pressure (4.7 mmHg/In(microgram/dl] at very low blood lead concentrations (2-21 micrograms/dl). This increase appears to result from negative confounding, particularly after taking into account tobacco use. Relations are even larger in blacks who infrequently use caffeine (16.7 and 10.4 mmHg/In(microgram/dl) for systolic and diastolic pressure, respectively). In contrast, a negative relation between systolic pressure and blood lead concentration (-5.7 mmHg/In(microgram/dl] is suggested in nonblack males (n = 117). These findings indicate that race, lead accumulation, and physiologic effects related to caffeine use (e.g., catecholamine effects) may interact to produce marked differences in effect on blood pressure.

 

Influence of race, tobacco use, and caffeine use on the relation between blood pressure and blood lead concentration
Sharp DS, Benowitz NL, Osterloh JD, Becker CE, Smith AH, Syme SL
Am J Epidemiol, 1990 May 131(5):845-54.

A number of studies have suggested a small to moderate positive relation between blood pressure and blood lead concentration in males (2-4 mmHg/In(microgram/dl]. However, this 1986 study of San Francisco bus drivers suggests larger relations in black males (n = 132) for both systolic pressure (7.5 mmHg/In(microgram/dl] and diastolic pressure (4.7 mmHg/In(microgram/dl] at very low blood lead concentrations (2-21 micrograms/dl). This increase appears to result from negative confounding, particularly after taking into account tobacco use. Relations are even larger in blacks who infrequently use caffeine (16.7 and 10.4 mmHg/In(microgram/dl) for systolic and diastolic pressure, respectively). In contrast, a negative relation between systolic pressure and blood lead concentration (-5.7 mmHg/In(microgram/dl] is suggested in nonblack males (n = 117). These findings indicate that race, lead accumulation, and physiologic effects related to caffeine use (e.g., catecholamine effects) may interact to produce marked differences in effect on blood pressure.

 

Consistent pattern of elevated symptoms in air-conditioned office buildings: a reanalysis of epidemiologic studies
Mendell MJ, Smith AH
Am J Public Health, 1990 Oct 80(10):1193-9.

Published studies of the relation between type of building ventilation system and work-related symptom prevalence in office workers have been contradictory. A reanalysis was performed of six studies meeting specific eligibility criteria, combining published data with unpublished information obtained from study authors. Five eligible studies were from the United Kingdom, and one was from Denmark. Standardized categories of building ventilation type were created to allow comparison of effects across studies. Within each study, prevalence odds ratios (PORs) were calculated for symptoms in each ventilation category relative to a baseline category of naturally ventilated buildings. Air-conditioned buildings were consistently associated with increased prevalence of work-related headache (POR = 1.3-3.1), lethargy (POR = 1.4-5.1), and upper respiratory/mucus membrane symptoms (POR = 1.3-4.8). Humidification was not a necessary factor for the higher symptom prevalence associated with air-conditioning. Mechanical ventilation without air-conditioning was not associated with higher symptom prevalence. The consistent associations found between type of building ventilation and reported symptom prevalence have potentially important public health and economic implications.

 

The importance of the hazard identification phase of health risk assessments illustrated with antimony emissions from waste incineration facilities
Smith AH, Goeden H, Frisch J
In: Bonin JJ, Stevenson DE (eds):
Advances in Risk Analysis, vol 7, New York: Plenum Press, 1989; 539-43.

In the course of conducting a health risk assessment for emissions from municipal waste incineration facilities, the literature was reviewed for a variety of emissions which have previously been regarded as non-carcinogenic. The objective was to establish the lowest levels of exposure causing toxic effects in animals and humans with view toward calculating safely margins with projected exposure levels. A journal paper was found reporting that antimony exposure caused lung cancer in rats. The same paper referenced a dissertation study with a similar finding. A report was subsequently found indicating lung cancer excess among smelter workers exposed to antimony, although no journal publications were found for this study. This paper presents a dose-response analysis for the animal and human data. The human data analysis suggested that antimony has a cancer potency of the same order as that which the U.S. Environmental Protection Agency has published for nickel. However, the animal data suggested a much higher cancer potency. These cancer potency figures were included in cancer risk characterization of emissions from the facility. While antimony turned out not to the a major contributor to the overall cancer risk estimates for the municipal waster incineration facilities, the discovery that it is a probable human carcinogen illustrates the importance of the hazard identification phase of health risk assessments.

 

 

Epidemiological studies of cancer and pesticide exposure
Smith AH, Bates MN
In:
196th National Meeting of the American Chemical Society, Los Angeles, CA, September 25-30 1989; 207-22.

Epidemiological data are often rejected for risk assessment purposes because of the lack of accurate exposure data. Animal data are frequently resorted for risk assessment calculations. Such a decision should account for potential errors in animal to human risk extrapolations, which may be of 1 or 2 orders of magnitude or more. Because historical human exposure can usually be estimated with confidence that the errors would be considerably less than 1 order of magnitude, it follows that human studies should generally take precedence over animal studies, even when crude assumptions have to be made concerning human exposure levels.

This paper illustrates this with cancer risk assessments for vinyl chloride and antimony, both of which relied on use of the stipulated average cohort exposure levels without use of any individual exposure data for cohort members. Linear extrapolations of risk to low exposures were used in both instances. Non-cancer risk assessments were illustrated by examining results of experimental studies of effects of ozone on ventilatory function. A simple approach, in this case involving visual inspection of study results, was again recommended. Consideration was given to concerns about synergistic effects of low-level exposure to chemical mixtures. Calculations were presented to demonstrate that estimating risks by multiplying effects of individual chemicals produces the same risk estimated by adding effects, provided that exposure levels were sufficiently low for each individual agent.

It was concluded that epidemiology has much to offer to environmental health risk assessment, but that epidemiologists need to be more effective in justifying the scientific basis of the design and interpretation of epidemiological studies to laboratory scientists, who frequently reject epidemiological findings for inappropriate reasons.

 

Asbestos and kidney cancer: the evidence supports a causal association
Sharp DS, Osterloh J, Becker CE, Smith AH, Holman BL, Fisher JM
Arch Environ Health, 1989 16(2): 159-66.

The role of asbestos in the etiology of lung cancer and of mesothelioma of the pleura and peritoneum has been well documented. The evidence for a causal association between asbestos and other human cancers is not as extensive but suggests that asbestos may be carcinogenic at several different sites. This paper is concerned specifically with a possible causal association between asbestos and human kidney cancer. A review of the evidence to date indicates that only three human studies have sufficient statistical power to detect an excess mortality from kidney cancer among workers exposed to asbestos. All three were occupational cohort studies, and two of these gave strong direct evidence for such an excess; a study of U.S. insulators (kidney cancer SMR = 2.22, 90% CI 1.44-3.30), and a study of U.S. asbestos products company workers (kidney cancer SMR = 2.76, 90% CI 1.29-5.18). The third study, of Italian shipyard workers, reported excess mortality from "cancers of the kidney, urinary bladder, and other urinary organs" (SMR = 1.98, 90% CI 1.42-2.70). Further support for a causal association includes studies finding asbestos fibers in human kidneys and urine, as well as reports of kidney tumors in two animal bioassays. It is concluded that asbestos should be regarded as a probable cause of human kidney cancer.

 

 

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