Diabetes Treatments

Living with diabetes makes it even who have diabetes are more likely Some people with diabetes may have nerve damage in the. feet, causing …

Environmental Contaminants as Etiologic Factors for Diabetes
Matthew P Longnecker and Julie L Daniels
Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina USA

For both type 1 and type 2 diabetes mellitus, the rates have been increasing in the United States and elsewhere; rates vary widely by country, and genetic factors account for less than half of new cases These observations suggest environmental factors cause both type 1 and type 2 diabetes Occupational exposures have been associated with increased risk of diabetes In addition, recent data suggest that toxic substances in the environment, other than infectious agents or exposures that stimulate an immune response, are associated with the occurrence of these diseases We reviewed the epidemiologic data that addressed whether environmental contaminants might cause type 1 or type 2 diabetes For type 1 diabetes, higher intake of nitrates, nitrites, and N-nitroso compounds, as well as higher serum levels of polychlorinated biphenyls have been associated with increased risk Overall, however, the data were limited or inconsistent With respect to type 2 diabetes, data on
arsenic and 2,3,7,8-tetrachlorodibenzo-pdioxin relative to risk were suggestive of a direct association but were inconclusive The occupational data suggested that more data on exposure to N-nitroso compounds, arsenic, dioxins, talc, and straight oil machining fluids in relation to diabetes would be useful Although environmental factors other than contaminants may account for the majority of type 1 and type 2 diabetes, the etiologic role of several contaminants and occupational exposures deserves further study Key words : arsenic, diabetes mellitus, epidemiology, nitrates, nitrites, nitroso compounds, occupations, polychlorinated biphenyls, tetrachlorodibenzodioxin — Environ Health Perspect 109suppl 6:871876 2001 http://ehpnet1niehsnihgov/docs/2001/suppl-6/871-876longnecker/abstracthtml

Our charge was to assess whether monitoring of diabetes rates could be used as a method for detecting community exposure to critical pollutants This question arose from the observation that the frequency of hospital admissions for diabetes varied substantially among several areas Areas of Concern on the border of the United States and Canada 1 The possibility that a corresponding distribution of
toxic substances might account for the variation was suggested by scientists at the International Joint Commission, who advise the two governments on the Great Lakes Water Quality Agreement 2 We responded to their charge by reviewing data on whether environmental factors might be responsible for variation in rates of diabetes The notion that environmental contaminants could increase risk of diabetes is fairly new 35 That occupational exposure could increase risk, however, has been recognized since the 1970s, when an association with carbon disulfide was reported 6 Here we review the relevant epidemiologic data, which can be categorized as follows: type 1 diabetes in relation to nitrates, nitrites, and nitrosamines, and in relation to polychlorinated biphenyls PCBs; and type 2 diabetes in relation to arsenic, 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD, and occupational exposures We included occupational exposures in our review because they could affect local disease rates if the area around the industry were polluted or if a large
Environmental Health Perspectives

proportion of the work force in a given area were employed by one industry We begin with a brief description of the main
types of diabetes and their epidemiology Type 1 diabetes results from decreased insulin production by the pancreatic cells -cell deficiency is due to autoimmune processes, or, in some cases, to idiopathic destruction 7 The autoimmune process against cells is thought to be triggered by a combination of genetic predisposition and environmental factors The concordance of type 1 diabetes among monozygotic twins is 2035 8,9, suggesting that environmental factors play a large role in the etiology The environmental factors usually considered etiologically relevant are infectious agents or dietary factors that stimulate an immune response 10 Poisonings with the rodenticide Vacor Rohm and Haas Co, Philadelphia, PA, however, have caused type 1 diabetes 11 Furthermore, certain drugs, such as pentamidine, can be toxic to cells 12 Agents that cause type 1 diabetes in animal models act through a variety of mechanisms 13, though all rely on toxins fairly specific for pancreatic cells, such as alloxan and streptozotocin Vacor, alloxan, and streptozotocin all include a urea structure; streptozotocin is also an N-nitroso compound The onset of type 1 diabetes is typically before adulthood The
incidence in whites is greater than in blacks or Asians 14 The incidence of type 1 diabetes has been increasing

worldwide for approximately 40 years, with an average yearly increase in incidence of 3 15 A typical incidence rate is 10/10 5 person-years world population standard, though rates vary markedly and are much higher in selected developed countries Clustering of cases of type 1 diabetes, diagnosed among children who were together during a defined period, further supports an environmental component to the etiology 1618 These cluster studies, however, offer little that allows one to distinguish the effect of contaminants from those of infectious agents or exposures that stimulate an immune response Type 2 diabetes is due to resistance to insulin action and a relative deficiency of insulin Age, obesity, central adiposity, lack of physical activity, and dietary glycemic load are the main factors identified as responsible for the disease 19 The concordance rate among monozygous twins is about 30 9 Whether chemical agents can cause type 2 diabetes in humans is not as clearly established as for type 1 diabetes, though suggestive data exist 6 Many drugs, however, exacerbate type 2
diabetes 20 As with type 1 diabetes, animal models of type 2 diabetes rely on a variety of mechanisms, and many include an element of impaired insulin action 21 The onset of type 2 diabetes is typically during adulthood Disease is more frequent among blacks, MexicanAmericans, and Native Americans 14 The prevalence of diabetes of all types was 65 in the United States in 1998 22, with approximately 9095 of cases due to type 2 diabetes 23 The prevalence of type 2 diabetes in the United States has increased by 33 during the past decade 22,23 This increase has been attributed to the rise in the prevalence of obesity 22 Worldwide the prevalence of type 2 diabetes varies roughly 10-fold, and the number of people with diabetes has increased 11 in the past 5 years 24

This article is based on a presentation at the Workshop on Methodologies for Community Health Assessment in Areas of Concern held 45 October 2000 in Windsor, Ontario, Canada Address correspondence to MP Longnecker, NIEHS EB, PO Box 12233, MD A3-05, Research Triangle Park, NC 27709-2233 USA Telephone: 919 541-5118 Fax: 919 541-2511 E-mail: longnecker@ niehsnihgov Received 28 March 2001; accepted 12 July 2001

VOLUME 109 |
SUPPLEMENT 6 | December 2001

871

Longnecker and Daniels

Regardless of type, patients with diabetes mellitus are at increased risk of small and large blood vessel disease and hyperlipidemia, resulting in retinopathy, neuropathy, vascular diseases such as myocardial infarction, stroke, aneurysm, and kidney failure, and they are also at increased risk of depression 25 The cost of diabetes in the United States in 1992 was estimated at 90 billion 26 For both type 1 and type 2 diabetes, genetic factors by themselves appear to account for less than half of the disease; incidence rates have increased over relatively short periods, and incidence rates vary widely across geographic areas These observations suggest that environmental factors, broadly defined, account for much of the disease 27 Temporal and spatial variations in disease frequency, however, are nonspecific with respect to the etiologic agents involved 28 Because environmental contaminants that are diabetogenic in humans are plausible, we will consider the evidence that any might be associated with risk of diabetes In our discussion we briefly address whether the variation in rates of diabetes in the Areas of Concern might be
related to the contaminants identified in this review

Potential Risk Factors for Type 1 Diabetes
Nitrates, Nitrites, and Nitrosoamines
In the gastrointestinal tract, nitrates can be converted to nitrites, and nitrites can react with amines to form N-nitroso compounds Because of this interrelatedness, we have considered the data for these nitrogencontaining compounds together Drinking water can be contaminated with nitrates resulting from fertilizer application Foods contain nitrates, nitrites, and N-nitroso compounds In 1981 Helgason and Jonasson 29 first drew attention to the possibility that N-nitroso compounds may cause type 1 diabetes in humans Consumption early in pregnancy of cured mutton, a source of N-nitroso compounds, was followed by a high incidence of type 1 diabetes in male offspring They proposed that dietary nitrosamine activity was inhibited by estrogen and promoted by testosterone, as with streptozotocin, thus accounting for the male specificity Helgason et al 30 subsequently induced diabetes in the progeny of mice fed N-nitrosoladen mutton, and males were preferentially affected Subsequent in vitro work revealed

Table 1 Summary of results from ecologic studies
of average water nitrate levels in relation to incidence of type 1 diabetes First author, year Kostraba, 1992 3 Parslow, 1997 32 Site Colorado, United States Yorkshire, United Kingdom The Netherlands Number of geographic units 63 Counties 148 Water supply zones 3,932 Postal code areas Exposure levels mg/L 0 82 15 32 32 149 149 410 10 10 25 25 Results
r 023

Comments
p 007; 2

influential counties RR 1 RR 11 RR 13 RR 1 RR 10 RR 15

Van Maanen, 2000 33

Abbreviations: r, Pearson correlation coefficient; RR, relative risk p 005

Table 2 Summary of results from casecontrol studies of dietary nitrates, nitrites, and nitrosamines in relation to type 1 diabetes First author, year Dalquist, 1990 35 Site Sweden Number of cases 339 Exposure Nitrosamine in food Nitrate and nitrite in food Exposure quartile 1 23 4 1 23 4 1 2 3 4 1 2 3 4 1 2a 3 Odds ratio 1 17 26 1 08 24 1 12 15 23 1 08 10 09 1 07 11

that selected N-nitroso compounds were especially toxic to pancreatic cells 31 Associations between regional water nitrate levels and the incidence of type 1 diabetes have been reported in three ecologic studies Table 1 Kostraba et al 3 found a positive correlation even though the range
of average nitrate levels was relatively limited The association, however, appeared to be influenced greatly by data from one or two counties Parslow et al 32 reported that the rate of diabetes was 30 higher among those in water supply zones with average nitrate levels of 14940 mg/L compared with those in areas with means less than 32 mg/L Van Maanen et al 33 reported a 50 increase in rates when nitrate levels exceeded 25 mg/L, compared with levels less than 10 mg/L, though the confidence interval CI for this increase was wide and included one The average nitrate concentrations in all areas of all three studies were below the current World Health Organization standard 50 mg/L 34 Although the data from these studies are consistent with the nitrate hypothesis, they provide only modest support because of the possibility that correlates of water nitrate level could account for the associations observed This possibility is better addressed by data from casecontrol studies In addition, drinking water exposure data could possibly be improved if seasonal variation in nitrate levels were assessed Data from casecontrol studies on childrens dietary intakes of nitrogencontaining compounds and
type 1 diabetes 3537 show a mixture of results Table 2 Virtanen et al 36 estimated intake of nitrate and nitrite from drinking water and found no relation with risk not shown in table The intake of nitrates and nitrites from food was much greater than from water 36 Because the absolute intake of Nnitroso compounds, nitrates, and nitrites was not reported in most studies 35,37, it is possible that low exposure levels in some studies was responsible for lack of association 37 A further uncertainty is whether nitrate is equally toxic in food and in water In summary, some data suggest an association between intake of nitrogen-containing compounds and risk of type 1 diabetes Overall, however, the data are limited and inconsistent

Virtanen, 1993 36

Finland

684

Nitrite in food

Polychlorinated Biphenyls
In a recent small study of pregnant women, serum levels of PCBs were 30 higher among those with diabetes primarily type 1 than among those without 38 Because the study was cross-sectional, whether the association was causal could not be determined If the association is confirmed by others, studies designed to assess whether the association is causal would be in order

Nitrate in
food

Verge, 1994 37

Australia

217

Nitrosamine in food

aVerge

et al 37 used tertiles p 005

872

VOLUME

109 | SUPPLEMENT 6 | December 2001 Environmental Health Perspectives

Environmental contamination and diabetes

Potential Risk Factors for Type 2 Diabetes
Arsenic
Epidemiologic data for populations with high exposure to arsenic, including selected industrial groups, are generally consistent with an increased risk of type 2 diabetes Table 3 In several studies of other populations with high arsenic exposure, investigators have not specifically reported results for diabetes 4447, raising the possibility that no notable associations were present Compared with the arsenic exposure levels among the populations represented in Table 3 4,39,40, exposure levels in the general US population are much lower, with a mean drinking water level of about 0001 mg/L 48 Within the United States, some areas have higher levels of exposure, for example, in parts of Utah where the average water arsenic levels are roughly 01 mg/L 49 A study among the Utah population that had increased exposure 49 showed that the overall rate of death from diabetes was not increased compared with the rate from the
rest of Utah Arsenic is metabolized in vivo to trivalent arsenic A trivalent arsenical, phenylarsine oxide, has adverse effects on the insulin receptor and glucose transport in in vitro experiments 50 The available epidemiologic data on arsenic and diabetes are suggestive but inconclusive because of the limited number of studies, their small size, and the possibility of publication bias The available data do not address the doseresponse issue in detail If arsenic exposure via drinking water does increase risk of type 2 diabetes, this may occur only among those consuming water with an arsenic concentration of more than 01 mg/L This is potentially an extremely serious problem in Bangladesh, where up to 30 million people may be drinking arseniccontaminated water 51

Table 3 Risk of type 2 diabetes in groups highly exposed to arsenic relative to less-exposed groups, by type of exposure First author, year Exposure via drinking water Tseng, 2000 39 Tsai, 1999 40 Rahman, 1998 4 Occupational exposure Rahman, 1995 41 Rahman, 1996 42 Bartoli, 1998 43
aApproximate bAmong

Number of Place or type exposed cases Taiwan Taiwan Bangladesh Copper smelter Glass workers Glass workers 41 188 21 10 31
3

Mean exposure levela,b 08 mg/L water 08 mg/L water 05 mg/L water 05 mg/m3 air Unknown Unknown

RR a 4 14 6 4 14 034d

Study design Ecologic Ecologicc Cross-sectional Nested casecontrol Nested casecontrol Occupational cohort

the exposed group cThe subjects in the Tseng et al study 39 and Tsai et al study 40 overlapped somewhat Putai Township dValue shown is reported SMR/100p 005

Table 4 Description of studies on TCDD in relation to type 2 diabetes or hyperglycemia Number exposed With Total diabetes 55 200 134 158 989 281 11 10 146 26 132 33 89 169

First author, year Pazderova-Vejlupkova, 1981 52 Suskind, 1984 53 Ott, 1994 54 Zober, 1994 55 Henriksen, 1997 56 Calvert, 1999 57 Pesatori, 1998 58 Vena, 1998 59 Steenland, 1999 60 Longnecker, 2000 5 Cranmer, 2000 61

Exposure level High High High High Medium High High High High Low Lowmoderate

Association

Outcome GTTa Glucose Glucose Diabetes Diabetes, GTT Diabetes, glucose Mortalityb Mortality Mortality Diabetes, GTT Insulin, GTTc

1,197 69

Abbreviations: , inverse relation; , no association; , equivocally positive association; , unequivocally positive association aStudy design was case series; n 1 based on
one-fifth of cases with abnormal GTT bResults for females were unequivocally positive cIncreased insulin level was the positive finding

2,3,7,8-Tetrachlorodibenzo-p-dioxin
We identified 11 reports that addressed the relation of TCDD with type 2 diabetes, hyperglycemia, or hyperinsulinemia Table 4 Most of the studies were of workers exposed to TCDD 5255,57,59,60 Cranmer et al 61 studied community members living near a toxic waste disposal site, and Pesatori et al 58 reported on the experience of those living near a TCDD-laden plume resulting from an out-of-control reaction in a chemical plant Vietnam veterans exposed to TCDD in Agent Orange were the subjects in the report by Henriksen et al 56 A group of veterans not exposed to Agent Orange were the subjects in the report by Longnecker and Michalek 5 We excluded from this review two studies that examined diabetes in veterans who had served
Environmental Health Perspectives

in the Vietnam War but for whom no serum TCDD levels were available 62,63 Most Vietnam veterans were not exposed to TCDD more than other groups with background-level exposure 64,65; exceptions were veterans in the Chemical Core and in Operation Ranch Hand who
came in contact with Agent Orange The results of the 11 studies were categorized according to type of outcome and exposure level Table 5 Of the studies showing an unequivocally positive association, none are very convincing on close examination The results from the Seveso study 58 were unequivocally positive among women but not among men The relative risk of 19 95 CI, 1132 among the highly exposed women in Zone B was adjusted for age but not other risk factors The group of highly exposed Czech workers mean age 46 years 52 had a higher prevalence of diabetes than those 2079 years of age in the Czech Republic 24 But in the absence of a statistical comparison of prevalences and the possibility that confounding factors accounted for the increase, whether the prevalence of diabetes was notably greater than expected remains in doubt Although the study by Henriksen et al 56 was a cohort study, the TCDD serum levels used to assess exposure were measured

Table 5 A tally of study results on TCDD in relation to type 2 diabetes or hyperglycemiaa Mortality studies Mediumhigh exposed Morbidity studies Lowmoderate exposed Mediumhigh exposed Association | | | || ||

|

|

||

Abbreviations: ,
inverse relation; , no association; , equivocally positive association; , unequivocally positive association aThe studies from which results were tallied are listed in Table 4

within a few years of when diabetes and related outcomes were ascertained Thus, if diabetics or subjects with subclinical glucose intolerance had a slower rate of excretion of TCDD, this could account for the association observed 66 Furthermore, the prevalence of diabetes in veterans exposed to Agent Orange was not greater than in the unexposed comparison group The results from the study by Longnecker and Michalek 5 suffer from the same weakness outlined for the study by Henriksen et al 56 The positive finding in the study by Cranmer et al 61 was an association of TCDD level with hyperinsulinemia on a glucose tolerance test GTT Although this is consistent with a TCDDtype 2 diabetes relation, no association with glucose was found

VOLUME 109 | SUPPLEMENT 6 | December 2001

873

Longnecker and Daniels

Several of the studies with equivocally positive results also have notable weaknesses The populations studied by Ott et al 54 and Zober et al 55 were basically the same, but the results of these two studies
appear to be inconsistent with each other Table 4 Calvert et al 57 found that the workers with the highest serum TCDD levels also had the highest serum glucose levels compared with those of an unexposed group, but within the group of exposed workers there was no doseresponse relation between TCDD levels and serum glucose or prevalence of diabetes Overall, the data on TCDD exposure in relation to diabetes and hyperglycemia are mixed Compelling studies supporting a causal effect of TCDD on diabetes are absent We note, however, that Enan et al 67 have shown that TCDD decreases cellular glucose update, thus a diabetogenic effect of TCDD is biologically plausible

Occupational Exposures
In this section we review data on diabetes in relation to occupational exposures Data for workers exposed to arsenic and TCDD, however, were considered above with the relevant nonoccupational data The statistical power of occupational mortality studies, such as those shown in Table 6, to detect increases due to diabetogenic exposures is limited because a reporting of diabetes on death certificates is highly variable and death certificates reflect less than half of the diabetes among the deceased 80, b
the assessment of exposure may lack sufficient detail, and c the number of exposed subjects who develop diabetes is relatively small in typical occupational cohort studies In addition, exposures in the occupational setting are generally mixed and not specific with respect to toxic substances implicated Among rubber workers, a moderately increased mortality from diabetes was reported in two cohorts 68,69,81 Two subgroups of rubber workers were identified by McMichael and colleagues 69,81 as having

the greatest risk of diabetes: a those in inspection, finishing, and repair, and b those in janitoring, trucking, power plant, and test driving In the report by Andjelkovic et al 69, the overall standardized mortality ratio SMR for diabetes was only slightly elevated at 117, but when the deaths occurring only during retirement were considered, the SMR was 135 p 005 Similarly, Weiland and colleagues 70 found that mortality from diabetes was greater among retired rubber workers SMR 181; 95 CI, 131244 than among active workers SMR 152; 95 CI, 112201 The greater risk of occupationassociated diabetes seen after retirement 69,70 fits with the hypothesis that an occupation-induced
susceptibility to type 2 diabetes could be unmasked by the increased sedentarism and obesity that accompany retirement Exposure to N-nitroso compounds in the rubber industry has been high 82, although exposure to other agents such as naphthylamine, benzene, polycyclic aromatic hydrocarbons, solvents, fumes from vulcanization, and talc has also been frequent Data on mortality from diabetes among pulp and paper mill workers have been presented in three reports 7173, with a moderate excess of diabetes evident in two 71,72 Although exposure to numerous chemicals and other substances occurs in the pulp and paper industry, potentially notable agents are dioxins and talc Among a group of chemical industry workers, deaths from diabetes were double the expected number 74 Among the many exposures in that group, none were specifically linked to diabetes In a smaller study among chemical and refinery workers, there was no overall excess of diabetes 75 Among the subset who did at least some work in the chemical plant, however, an SMR of 173 was found, although this was not statistically significant three observed cases Dry-cleaning workers have been exposed to several solvents, with
tetrachloroethylene the main agent in use since the 1950s 77 In

Table 6 Summary of data on diabetes in selected occupational groups First author, year McMichael, 1974 68 Andjelkovic, 1976 69 Weiland, 1996 70 Schwartz, 1988 71 Wingren, 1991 72 Wong, 1996 73 Wong, 1984 74 Marsh, 1991 75 Katz, 1981 76 Blair, 1979 77 Park, 1996 78 Morgan, 1980 79
aProportional bOriginally

Industry/occupation Rubber Rubber Rubber Pulp, paper mill Pulp, paper mill Pulp, paper mill Chemical Chemical, refinery Laundry, dry cleaning Laundry, dry cleaning Engine manufacturing Pesticide users

Number of cases 43 48 49 22 46 17 19 9 25 9 25 58
cDDE/DDT

SMR 143 117 152 146,a 130,b 110 220 77 177,a 103a 150,a 100,c

the two studies of laundry and dry-cleaning workers reporting results specifically for diabetes, an excess of death from diabetes was found in one study 76 but not in a second smaller one 77 Excess mortality from diabetes was also found among workers involved in engine manufacturing 78 Exposure specifically to machining fluid was associated with increased risk Some machining fluids contain N-nitroso compounds, but the straight oils implicated in this study did not In a study of a group of
pesticide users and an unexposed group, Morgan et al 79 found that subjects with diabetes, compared with those without diabetes, had higher blood levels of 1,1,1-trichloro-2,2-bispchlorophenylethane DDT and its metabolite 1,1-trichloro-2,2-bisp-chlorophenyl ethylene DDE As with the studies of TCDD, the possibility exists that subjects with diabetes or prediabetes excreted organochlorines in this case DDT and DDE more slowly An excess of diabetes has also been reported among workers exposed to heat stress 83 and among those with sedentary occupations 81,84 Because these associations were likely due to confounding by body mass index or low physical activity, we considered them outside the scope of this review Trivalent chromium is an essential nutrient, and supplementation improves glucose tolerance in most clinical trials 85 A study of tannery workers occupationally exposed to chromium found a lower prevalence of impaired glucose tolerance and of diabetes mellitus than in the control group, even though the exposed workers were more obese; the results, however, were statistically significant only among workers more than 48 years of age 86 In other studies of chromium-exposed tannery
workers, investigators have generally not presented results for diabetes 87,88, although in one study exposed workers had an SMR of 130 95 CI, 67227 89 In summary, the occupational data show for both rubber and pulp and paper mill workers an excess of diabetes deaths in more than one study 68,7072, but results were mixed 69,73 Complete investigations of occupational risks would need to account for the level of physical activity and body mass index associated with a given exposure

Discussion
Environmental Contaminants and Increased Rates of Diabetes
Available data on drinking water nitrates do not exclude the possibility that nitrates affect risk of type 1 diabetes, but neither were they strongly supportive of an association More

mortality ratio presented as an odds ratio; here shown 100 levels in cases significantly higher than in controls No SMR or RR was presented, but presumably if one had been presented, it would be greater than 100 if expressed on a scale comparable with the others shown in the table p 005

874

VOLUME

109 | SUPPLEMENT 6 | December 2001 Environmental Health Perspectives

Environmental contamination and diabetes

data from casecontrol studies done in areas
where exposure to nitrates in water is unusually high would be particularly useful The association between PCBs and type 1 diabetes was reported in only one small crosssectional study The importance of this observation will be clearer if replicated by others, especially using a prospective design Data on health effects of arsenic were suggestive of an association with type 2 diabetes Additional reports on diabetes in groups consuming water contaminated with arsenic, where epidemiologic studies of other outcomes have already been done 4447, could be useful If an arsenic effect exists, however, it is likely to affect few populations because severe contamination is unusual TCDD appeared to be the only environmental contaminant identified that could be having widespread affects in the general population But data among populations with background-level exposure came from just two studies, each with limitations Prospective data on the relation between TCDD and type 2 diabetes are needed Although selected occupational exposures may increase risk of type 2 diabetes, few specific agents were implicated in our review Additional data on diabetes among those with exposure to N-nitroso
compounds, arsenic, TCDD, talc, and straight oil machining fluids would be of interest

of the Areas of Concern, had an increase in diabetes hospitalizations, is economically like Detroit, and could have this industry there Arsenic exposure from drinking water in the Areas of Concern would seem an unlikely culprit, but the possibility of occupational arsenic exposure might be worth investigating Similarly, substantial variation in contamination of the food supply with TCDD seems unlikely, but again, the possibility of occupational exposure may be worth considering

8 9

10

11

-Cell Toxins and Type 2 Diabetes
Type 1 and type 2 diabetes have no established risk factors in common see above In searching for new risk factors, however, it may be worthwhile to consider that there could be overlap in the risk factors for these two types of diabetes Both type 1 and type 2 diabetes have -cell insufficiency, to a greater or lesser extent, as part of their pathogenesis The -cell toxin streptozotocin, typically used to induce type 1 diabetes in animals, under certain conditions can cause type 2 diabetes 90 Thus, for example, examining nitrosamine intake as a risk factor for type 2 diabetes
could be worthwhile

12

13

14

15

16

17 18

Summary
With respect to variation in diabetes rates in the Areas of Concern, our review points to no obvious environmental contaminants that might explain the variation in diabetes rates Several occupations and occupational exposures were identified, however, that may have contributed In general terms regarding environmental contaminants as etiologic agents for diabetes, data on arsenic and TCDD were suggestive but inconclusive with respect to type 2 diabetes, and for type 1 diabetes data on intake of nitrates, nitrites, and N-nitroso compounds were less suggestive but not completely null Apart from the exposures considered in this review, other environmental contaminants could be related to risk of diabetes; however, no specific clues were uncovered in the epidemiologic literature
REFERENCES AND NOTES

19

Environmental Contaminants and Local Variation in Rates of Diabetes
The observation that prompted this review was that hospitalization rates for diabetes varied across the Areas of Concern 1 The great majority of diabetes is type 2; therefore, the variation in hospitalization rates is accounted for by corresponding variation either
in risk factors for type 2 diabetes or in the medical management of patients Given that relative body weight is such a strong risk factor for type 2 diabetes, it is highest among the potential suspects accounting for geographic variation in rates of diabetes Without the ability to take this and other such accepted risk factors for diabetes into account, it would be highly speculative to assume a high rate of diabetes in a given area was due to contamination Nonetheless, areas with higher rates of hospitalization could be those containing a substantial portion of the population occupationally exposed to a diabetogenic agent Among the studies where an occupation was associated with an increased rate of death from diabetes, however, the rate was at most doubled and was usually much lower An investigation of diabetes among workers involved in engine manufacturing, as in the Park and Mirer study 78, taking occupational physical activity into account, may be worthwhile Windsor, Ontario, Canada, one
Environmental Health Perspectives

20

21

22

23

24 25

26 27

28 1 Elliot S, Eyles J, DeLuca P Mapping health in the Great Lakes Areas of Concern: a user-friendly tool for policy and
decision makers Environ Health Perspect 109suppl 6:817826 2001 United States and Canada Great Lakes Water Quality Agreement, 1972 http://wwwonecgcca/glwqa [cited 9 November 2001] Kostraba JN, Gay EC, Rewers M, Hamman RF Nitrate levels in community drinking waters and risk of IDDM Diabetes Care 15:15051508 1992 Rahman M, Tondel M, Ahmad SA, Axelson O Diabetes mellitus associated with arsenic exposure in Bangladesh Am J Epidemiol 148:198203 1998 Longnecker MP, Michalek JE Serum dioxin level in relation to diabetes mellitus among Air Force veterans with background levels of exposure Epidemiology 11:4448 2000 Franco G, Malamani T, Piazza A Glucose tolerance and occupational exposure to carbon disulphide [Letter] Lancet 2:1208 1978 Wareham NJ, ORahilly S The changing classifiication and dia-

29 30

2

3

31

4

32

5

6

33

7

nosis of diabetes New classifiication is based on pathogenesis not insulin dependence Br Med J 317:359360 1998 Barnett AH, Eff C, Leslie RD, Pyke DA Diabetes in identical twins A study of 200 pairs Diabetologia 20:8793 1981 Kaprio J, Tuomilehto J, Koskenvuo M, Romanov K, Reunanen A, Eriksson J, Stengard J, Kesaniemi YA Concordance for type 1 insulin-dependent
and type 2 non-insulin-dependent diabetes mellitus in a population-based cohort of twins in Finland Diabetologia 35:10601067 1992 Dahlquist G Environmental risk factors in human type 1 diabetes–an epidemiological perspective Diabetes Metab Rev 11:3746 1995 Karam JH, Lewitt PA, Young CW, Nowlain RE, Frankel BJ, Fujiya H, Freedman ZR, Grodsky GM Insulinopenic diabetes after rodenticide Vacor ingestion: a unique model of acquired diabetes in man Diabetes 29:971978 1980 Assan R, Perronne C, Assan D, Chotard L, Mayaud C, Matheron S, Zucman D Pentamidine-induced derangements of glucose homeostasis Determinant roles of renal failure and drug accumulation A study of 128 patients Diabetes Care 18:4755 1995 Peschke E, Ebelt H, Bromme HJ, Peschke D Classical and new diabetogens–comparison of their effects on isolated rat pancreatic islets in vitro Cell Mol Life Sci 57:158164 2000 Nathan DM Diabetes mellitus In: Scientific American Medicine Rubenstein E, Federman DD, eds New York: Scientifiic American, 1997 Onkamo P, Vaananen S, Karvonen M, Tuomilehto J Worldwide increase in incidence of type 1 diabetes–the analysis of the data on published incidence trends Diabetologia 42:13951403 1999
Bodington MJ, Muzulu SI, Burden AC Spatial clustering in childhood diabetes: evidence of an environmental cause Diabet Med 12:865867 1995 Dahlquist GG, Kallen BA Time-space clustering of date at birth in childhood-onset diabetes Diabetes Care 19:328332 1996 Law GR, McKinney PA, Staines A, Williams R, Kelly M, Alexander F, Gilman E, Bodansky HJ Clustering of childhood IDDM Links with age and place of residence Diabetes Care 20:753756 1997 ORahilly S Science, medicine, and the future Non-insulin dependent diabetes mellitus: the gathering storm Br Med J 314:955959 1997 National Diabetes Data Group Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance Diabetes 28:10391057 1979 Kadowaki T Insights into insulin resistance and type 2 diabetes from knockout mouse models J Clin Investig 106:459465 2000 Mokdad AH, Ford ES, Bowman BA, Nelson DE, Engelgau MM, Vinicor F, Marks JS Diabetes trends in the US: 1990-1998 Diabetes Care 23:12781283 2000 Trends in the prevalence and incidence of self-reported diabetes mellitus–United States, 1980-1994 Morb Mortal Wkly Rep 46:10141018 1997 International Diabetes Federation Diabetes Atlas 2000 Brussels,
Belgium:International Diabetes Federation, 2000 Bloomgarden ZT European Association for the Study of Diabetes Annual Meeting, 1999: complications of diabetes Diabetes Care 23:14231428 2000 Mandrup-Poulsen T Diabetes Br Med J 316:12211225 1998 Diabetes Epidemiology Research International Preventing insulin dependent diabetes mellitus: the environmental challenge Br Med J Clin Res Ed 295:479481 1987 Morgenstern H Ecologic studies in epidemiology: concepts, principles, and methods Annu Rev Public Health 16:6181 1995 Helgason T, Jonasson MR Evidence for a food additive as a cause of ketosis-prone diabetes Lancet 2:716720 1981 Helgason T, Ewen SWB, Ross IS, Stowers JM Diabetes produced in mice by smoked/cured mutton Lancet 2:10171022 1982 Wilson GL, Mossman BT, Craighead JE Use of pancreatic beta cells in culture to identify diabetogenic N-nitroso compounds In Vitro 19:2530 1983 Parslow RC, McKinney PA, Law GR, Staines A, Williams R, Bodansky HJ Incidence of childhood diabetes mellitus in Yorkshire, northern England, is associated with nitrate in drinking water: an ecological analysis Diabetologia 40:550556 1997 van Maanen JM, Albering HJ, de Kok TM, van Breda SG, Curfs DM, Vermeer IT,
Ambergen AW, Wolffenbuttel BH, Kleinjans JC, Reeser HM Does the risk of childhood diabetes mellitus require revision of the guideline values for nitrate in drinking

VOLUME 109 | SUPPLEMENT 6 | December 2001

875

Longnecker and Daniels

water Environ Health Perspect 108:457461 2000 34 WHO Inorganic constituents and physical parameters In: Guidelines for Drinking Water Quality, Vol 2: Health Criteria and Other Supporting Information, 2nd ed Geneva:World Health Organization, 1996;313324 35 Dahlquist GG, Blom LG, Persson L, Sandstrom AIM, Wall SGI Dietary factors and the risk of developing insulin dependent diabetes in childhood Br Med J 300:13021306 1990 36 Virtanen SM, Jaakkola L, Rasanen L, Ylonen K, Aro A, Lounamaa R, Akerblom HK, Tuomilehto J Nitrate and nitrite intake and the risk for type 1 diabetes in Finnish children Childhood Diabetes in Finland Study Group Diabet Med 11:656662 1994 37 Verge CF, Howard NJ, Irwig L, Simpson JM, Mackerras D, Silink M Environmental factors in childhood IDDM A population-based, case-control study Diabetes Care 17:13811389 1994 38 Longnecker MP, Klebanoff MA, Brock JW, Zhou H Polychlorinated biphenyl serum levels in pregnant subjects with
diabetes Diabetes Care 24:10991101 2001 39 Tseng CH, Tai TY, Chong CK, Tseng CP, Lai MS, Lin B, Chiou HY, Hsueh YM, Hsu KH, Chen CJ Long-term arsenic exposure and incidence of non-insulin-dependent diabetes mellitus: a cohort study in arseniasis-hyperendemic villages in Taiwan Environ Health Perspect 108:847851 2000 40 Tsai SM, Wang TN, Ko YC Mortality for certain diseases in areas with high levels of arsenic in drinking water Arch Environ Health 54:186193 1999 41 Rahman M, Axelson O Diabetes mellitus and arsenic exposure: a second look at case-control data from a Swedish copper smelter Occup Environ Med 52:773774 1995 42 Rahman M, Wingren G, Axelson O Diabetes mellitus among Swedish art glass workers–an effect of arsenic exposure? Scand J Work Environ Health 22:146149 1996 43 Bartoli D, Battista G, De Santis M, Iaia TE, Orsi D, Tarchi M, Pirastu R, Valiani M Cohort study of art glass workers in Tuscany, Italy: mortality from non-malignant diseases Occup Med 48:441445 1998 44 Smith AH, Goycolea M, Haque R, Biggs ML Marked increase in bladder and lung cancer mortality in a region of Northern Chile due to arsenic in drinking water Am J Epidemiol 147:660669 1998 45 Hopenhayn-Rich C,
Biggs ML, Smith AH Lung and kidney cancer mortality associated with arsenic in drinking water in Cordoba, Argentina Int J Epidemiol 27:561569 1998 46 Cuzick J, Sasieni P, Evans S Ingested arsenic, keratoses, and bladder cancer Am J Epidemiol 136:417421 1992 47 Tsuda T, Nagira T, Yamamoto M, Kume Y An epidemiological study on cancer in certified arsenic poisoning patients in Toroku Ind Health 28:5362 1990 48 IARC Some metals and metallic compounds IARC Monogr Eval Carcinog Risk Chem Hum 23:69 1980 49 Lewis DR, Southwick JW, Ouellet-Hellstrom R, Rench J, Calderon RL Drinking water arsenic in Utah: a cohort mortality study Environ Health Perspect 107:359365 107 50 Douen AG, Jones MN Phenylarsine oxide and the mechanism of insulin-stimulated sugar transport Biofactors 2:153161 1990 51 Hoque BA, Mahmood AA, Quadiruzzaman M, Khan F, Ahmed SA, Shafique SA, Rahman M, Morshed G, Chowdhury T, Rahman MM, et al Recommendations for water supply in arsenic mitigation: a case study from Bangladesh Public Health 114:488494 2000 52 Pazderova-Vejlupkova J, Lukas E, Nemcova M, Pickova J, Jirasek

53 54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

L The development and prognosis of
chronic intoxication by tetrachlordibenzo-p-dioxin in men Arch Environ Health 36:511 1981 Suskind RR, Hertzberg VS Human health effects of 2,4,5-T and its toxic contaminants JAMA 251:23722380 1984 Ott MG, Zober A, Germann C Laboratory results for selected target organs in 138 individuals occupationally exposed to TCDD Chemosphere 29:24232437 1994 Zober A, Ott MG, Messerer P Morbidity follow up study of BASF employees exposed to 2,3,7, 8-tetrachlorodibenzo-pdioxin TCDD after a 1953 chemical reactor incident Occup Environ Med 51:479486 1994 Henriksen GL, Ketchum NS, Michalek JE, Swaby JA Serum dioxin and diabetes mellitus in veterans of Operation Ranch Hand Epidemiology 8:252258 1997 Calvert GM, Sweeney MH, Deddens J, Wall DK Evaluation of diabetes mellitus, serum glucose, and thyroid function among United States workers exposed to 2,3,7,8-tetrachlorodibenzo-pdioxin Occup Environ Med 56:270276 1999 Pesatori AC, Zocchetti C, Guercilena S, Consonni D, Turrini D, Bertazzi PA Dioxin exposure and non-malignant health effects: a mortality study Occup Environ Med 55:126131 1998 Vena J, Boffetta P, Becher H, Benn T, Bueno-de-Mesquita HB, Coggon D, Colin D, Flesch-Janys D, Green L, Kauppinen
T, et al Exposure to dioxin and nonneoplastic mortality in the expanded IARC international cohort study of phenoxy herbicide and chlorophenol production workers and sprayers Environ Health Perspect 106suppl 2:645653 1998 Steenland K, Piacitelli L, Deddens J, Fingerhut M, Chang LI Cancer, heart disease, and diabetes in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin J Natl Cancer Inst 91:779786 1999 Cranmer M, Louie S, Kennedy RH, Kern PA, Fonseca VA Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD is associated with hyperinsulinemia and insulin resistance Toxicol Sci 56:431436 2000 CDC The Centers for Disease Control Vietnam Experience Study Health status of Vietnam veterans II: Physical health JAMA 259:27082714 1988 Commonwealth Department of Veterans Affairs Morbidity of Vietnam Veterans: a Study of the Health of Australias Vietnam Veteran Community Vol 1: Male Vietnam Veterans Survey and Community Comparison Outcomes Canberra:Commonwealth Department of Veterans Affairs, 1998 CDC The Centers for Disease Control Veterans Health Studies Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels in US Army Vietnam-era veterans JAMA 260:12491254 1988 Gladen BC, Longnecker MP,
Schecter AJ Correlations among polychlorinated biphenyls, dioxins, and furans in humans Am J Ind Med 35:1520 1999 Flanders WD, Lin L, Pirkle JL, Caudill SP Assessing the direction of causality in cross-sectional studies Am J Epidemiol 135:926935 1992 Enan E, Lasley B, Stewart D, Overstreet J, Vandevoort CA 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD modulates function of human luteinizing granulosa cells via cAMP signaling and early reduction of glucose transporting activity Reprod Toxicol 10:191198 1996 McMichael AJ, Spirtas R, Kupper LL An epidemiologic study of mortality within a cohort of rubber workers, 1964-72 J Occup Med 16:458464 1974 Andjelkovic D, Taulbee J, Symons M Mortality experience of a cohort of rubber workers, 1964-1973 J Occup Med 18:387394 1976

70 Weiland SK, Mundt KA, Keil U, Kraemer B, Birk T, Person M, Bucher AM, Straif K, Schumann J, Chambless L Cancer mortality among workers in the German rubber industry: 1981-91 Occup Environ Med 53:289298 1996 71 Schwartz E A proportionate mortality ratio analysis of pulp and paper mill workers in New Hampshire Br J Ind Med 45:234238 1988 72 Wingren G, Persson B, Thoren K, Axelson O Mortality pattern among pulp and paper
mill workers in Sweden: a case-referent study Am J Ind Med 20:769774 1991 73 Wong O, Ragland DR, Marcero DH An epidemiologic study of employees at seven pulp and paper mills Int Arch Occup Environ Health 68:498507 1996 74 Wong O, Brocker W, Davis HV, Nagle GS Mortality of workers potentially exposed to organic and inorganic brominated chemicals, DBCP, TRIS, PBB, and DDT Br J Ind Med 41:1524 1984 75 Marsh GM, Enterline PE, McCraw D Mortality patterns among petroleum refiiery and chemical plant workers Am J Ind Med 19:2942 1991 76 Katz RM, Jowett D Female laundry and dry cleaning workers in Wisconsin: a mortality analysis Am J Public Health 71:305307 1981 77 Blair A, Decouflle P, Grauman D Causes of death amng laundry and dry cleaning workers Am J Public Health 69:508511 1979 78 Park RM, Mirer FE A survey of mortality at two automotive engine manufacturing plants Am J Ind Med 30:664673 1996 79 Morgan DP, Lin LI, Saikaly HH Morbidity and mortality in workers occupationally exposed to pesticides Arch Environ Contam Toxicol 9:349382 1980 80 Andresen EM, Lee JA, Pecoraro RE, Koepsell TD, Hallstrom AP, Siscovick DS Underreporting of diabetes on death certifiicates, Kin County, Washington
Am J Public Health 83:10211024 1993 81 McMichael AJ, Spirtas R, Gamble JF, Tousey PM Mortality among rubber workers: relationship to specific jobs J Occup Med 18:178185 1976 82 Spiegelhalder B, Preussmann R Occupational nitrosamine exposure 1: rubber and tyre industry Carcinogenesis 4:11471152 1983 83 Wojtczak-Jaroszowa J, Jarosz D Health complaints, sicknesses and accidents of workers employed in high environmental temperatures Can J Public Health 77suppl 1:132135 1986 84 Morikawa Y, Nakagawa H, Ishizaki M, Tabata M, Nishijo M, Miura K, Kawano S, Kido T, Nogawa K Ten-year follow-up study on the relation between the development of non-insulindependent diabetes mellitus and occupation Am J Ind Med 31:8084 1997 85 Mertz W Chromium in human nutrition: a review J Nutr 123:626633 1993 86 Stupar J, Vrtovec M, Kocijancic A, Gantar A Chromium status of tannery workers in relation to metabolic disorders J Appl Toxicol 19:437446 1999 87 Takahashi K, Okubo T A prospective cohort study of chromium plating workers in Japan Arch Environ Health 45:107111 1990 88 Pastides H, Austin R, Lemeshow S, Klar J, Mundt KA A retrospective-cohort study of occupational exposure to hexavalent chromium Am J Ind
Med 25:663675 1994 89 Montanaro F, Ceppi M, Demers PA, Puntoni R, Bonassi S Mortality in a cohort of tannery workers Occup Environ Med 54:588591 1997 90 Hemmings SJ, Spafford D Neonatal STZ model of type II diabetes mellitus in the Fischer 344 rat: characteristics and assessment of the status of the hepatic adrenergic receptors Int J Biochem Cell Biol 32:905919 2000

876

VOLUME

109 | SUPPLEMENT 6 | December 2001 Environmental Health Perspectives