Long-Term Nonmalignant Disease Mortality in Subjects Exposed to Transmissible Agents Present in Animals Used for Food

Abstract

Objective:

To study mortality from nonmalignant diseases in subjects with high exposure to transmissible agents present in animals used for food, and in their raw or inadequately cooked products.

Methods:

Mortality was compared in a cohort of meat handlers in slaughtering and processing plants with that of the U.S. general population.

Results:

Excess mortality was observed for conditions known to be associated with infections—these include, septicemia, chronic nephritis, diseases of the kidney and ureter, diseases of the pancreas, cirrhosis of the liver, acute and subacute endocarditis, acute rheumatic fever, functional diseases of the heart, aortic aneurysm, intracranial and intraspinous abscess, and meningitis. Excess mortality was also observed for ischemic heart disease and diabetes, conditions without an established infectious etiology, but which have been linked with infections.

Conclusions:

If transmissible agents present in food animals and their raw products cause long-term diseases and mortality in humans, this study importantly points to the likely diseases, many of which are already known to be associated with infections. The excess mortality observed for ischemic heart disease and diabetes is consistent with existing evidence linking these conditions with infections, and gives rise to the novel hypothesis that microbial agents present in food animals and their products may be candidates for an infective role in the occurrence of these conditions, and therefore needs further investigation.

Introduction

Humans are commonly exposed to a plethora of transmissible agents present in animals used for food or in their raw or inadequately cooked products. These agents include prions (that cause Creutzfeldt-Jakob disease, bovine spongiform encephalopathy (“Mad Cow Disease”); viruses (influenza virus, West Nile encephalitis virus, and papilloma viruses); bacteria (C. tetanus, E. coli, salmonella, and brucella), chlamydia and rickettsia; fungi (aspergilla, cryptococcus); helminthes (tapeworm and roundworm); protozoa (toxoplasma, coccidia, and cryptosporidium); and innumerable similar agents that are associated with various malignant and nonmalignant diseases in the animals (Veterinary Medicine 2007). Outbreaks of zoonotic infections arising from these agents are common occurrences in the general population and in certain occupational groups (Encyclopedia of Occupational Health and Safety 1972, Veterinary Medicine 2007), and frequently present major public health problems.

However, while the short-term diseases that these exposures result in such as salmonellosis, E. coli infection, cryptosporidiosis, leptospirosis, and others have been well studied and documented in human populations for decades, usually because the clinical manifestation is acutely obvious or severe, it is not known (1) whether some of these agents after causing acute disease go on to later cause long-term disease many years thereafter, so that it is impossible to link the long-term effects with the initial infection; (2) whether some of these agents may not be known to be associated with any acute disease in humans because the initial infection is inapparent, but the organisms may persist within the body and later go on to produce disease many years later that is again impossible to link to the initial infection.

There are literally thousands of these different agents, and considering their numbers, the zoonotic disease potential in humans is known for relatively very few of them, and it is not known whether the vast majority cause any form of long-term disease in humans.

The study of long-term mortality in a group of subjects exposed to these agents in animal slaughtering and processing plants present a unique opportunity to answer this question for the following reasons.

(i) They represent a group with the highest known human exposure to these agents because of the sheer volume of animals they come into contact with (literally thousands of the live animals daily); they have intense contact with the blood, body secretions, feces, skin, internal organs, and raw products of these animals that carry the agents, on a daily basis; they get frequent penetrating injuries from power saws, sharp knives, or bone splinters that provide easy access to these agents directly into the blood; the workers frequently have scrapes, cuts, wounds, and dermatitis from irritating enzymes and proteins, and other body secretions, which provide ready access of these agents into the body through the skin (Encyclopedia of Occupational Health and Safety 1972); they are also exposed via the airborne route on a daily basis (Rahkio and Korkeala 1997). Thus, no other human group has such a potential for high exposure to these agents.

(ii) The population is well defined and much easier to follow-up in future for the occurrence of long-term effects than general population subjects.

(iii) There is a large exposure gradient within the group varying from those with little or no exposures to those with the highest exposures, making it easier to detect the effects of exposure, if any. This obviates the difficulty in using a general population group to study long-term effects of these agents in which virtually nearly everyone is exposed at low levels.

Because of this, we studied on two occasions mortality in a cohort of subjects in slaughterhouses and processing plants that handled cattle, pigs, and sheep who were identified from the rosters of the United Food & Commercial Workers (UFCW) union in Baltimore Maryland (Johnson 1987a, 1987b, 1989, Johnson et al. 2007). We reason that if these transmissible agents of food animals cause as yet unrecognized long-term diseases in humans, it will be readily seen in this highly exposed group and this cohort will provide important information on which are the conditions that may likely be candidates for this role. However, in both instances, either only a handful of conditions were examined, or only a minority of the cohort had died.

Here, we present an advanced update that more adequately and completely reflects the mortality experience of the group, because this time the majority (62%) of the cohort are now deceased, and 135 separate causes of death were investigated. Thus, this report is important because it is the only study to date that provides comprehensive information for the first time on long-term conditions that are likely to be associated with exposure to the transmissible agents of food animals.

Materials and Methods

The cohort consisted of all 8638 workers who were employed in 36 plants where cattle, pigs, and sheep were killed and/or processed. These plants were all located within the state of Maryland (all but two were in Baltimore). The workers studied at the time represented over 83% of the entire workforce employed in this industry in the state. We also studied a heterogeneous control group of 6,149 subjects in the same union, but who never worked in the meat industry, and were employed in soft drinks, oyster shucking, oyster and meat soup canning manufacturing plants, and so on. Both the meat and nonmeat workers represent all the workers in these groups that had ever been members of the union up to the time the study was started in 1979. No further update of their employment history was available after that date.

The workers who were studied initially paid union dues from July 1949 up to the end of 1979, and therefore information on duration of their employment in these plants was restricted to this period only. In the current report, they were followed up from January 1, 1950 till December 31, 2006, and during this period 5359 (62%) of them died. Various methods of follow-up were utilized and include use of the following: UFCW union membership and health insurance records; Social Security Administration Earnings and Benefit, and Mortality files; the National Death Index; Veterans Administration; Health Care Financing Administration; Maryland State Department of Motor Vehicles; newspaper obituary notices; funeral homes; personal contact by phone and mail; Polk and telephone directories; and a manual search of all the death certificate records at the Maryland State Department of Vital Records from 1949 to 1980 (Johnson et al. 1986).

The cause of death used in the analysis was the underlying cause as recorded in the death certificate. All deaths both in the study population and the reference U.S. mortality rates were coded to the 9th ICD Revision. Relative risks were estimated by the standardized mortality ratios (SMR) and proportional mortality ratios (PMR), using the United States general population rates for the period 1950–2006 for comparison. In the SMR analysis, the study population was stratified into four groups by sex and race (black males, black females, white males, and white females), and each of these groups was subdivided according to age at entry into the cohort (5-year intervals) and calendar year (5-year intervals). Person-years were accumulated from January 1, 1950 for those who were already members of the union before that date. For those who became members later, person-years started on the date of union membership (date of employment). Person-years were counted up to the date of death, or date of termination of the study on December 31, 2006.

Because of the exhaustive methods used to determine vital status (more than 92% of deaths detected) (Johnson et al. 1986, Johnson 1987a), subjects lost to follow-up were assumed to be alive at the end of follow-up. Expected deaths were obtained by multiplying the person-years in each cell by the corresponding sex, race-, calendar year-, and age-specific mortality rate of the U.S. population. Observed and expected deaths for each cell were summed over all ages and calendar years, and over all strata. The SMR is the total observed number of deaths divided by the total expected. A similar process of stratification was followed for estimating PMRs.

While all 5359 deceased subjects (62% of the study population) had complete information on race, gender, and date of birth as recorded in the death certificates, the remaining 3279 subjects (38%) not identified as deceased had no information on race, and their race was imputed based on the racial distribution of deceased subjects. We had previously reported that the racial distribution of deceased workers in this union was similar to that of half of the membership sampled during the first follow-up (Johnson et al. 1986). Moreover, sensitivity analyses in another cohort belonging to the same UFCW International Union did not reveal any serious bias using this approach (Johnson et al. 2010).

Results

The average follow-up for study subjects was 39 years, which is adequate for investigating both acute and chronic diseases. Although not shown, the results obtained from PMR analyses for which information on race was complete were very similar to those obtained in the SMR analyses in which race was imputed for nondeceased subjects. This close agreement suggests that no serious bias in the SMRs resulted from the missing data on race in nondeceased subjects. It should be noted that the risk estimates given by the SMRs in this study are conservative, as lost subjects were assumed to be alive. There were 593 subjects born in 1906 or earlier, who would have been at least 100 years old at the end of follow-up in 2006. Of these, 543 (92%) were known to be deceased, indicating that the successful follow-up rate of over 92% achieved in the past follow-ups is still being maintained (Johnson et al. 1986).

Of the 134 noncancer causes of death examined (listed in Johnson et al. 2010), we report in Table 1 the results for causes for which a statistically significant result was obtained in the cohort as a whole, or in any race/sex subgroups.

Table 1.

Standardized Mortality Ratios for Selected Nonmalignant Diseases for the Period 1950 to 2006—–Baltimore Cattle, Pig, and Sheep Abattoir and Meat Processing Plant Workers

Cause of death	White males (N = 5037)	Nonwhite males (N = 1632)	All males (N = 6669)	White females (N = 1855)	Nonwhite females (N = 114)	All females (N = 1969)	All whites (N = 6892)	All nonwhites (N = 1746)	All groups (N = 8638)	Nonmeat plants (N = 6149)
	Observation
Nonmalignant diseases	SMR (95% CI)
Intestinal infectious diseases (ICD 001–009)	2	1	3	3	0	3	5	1	6	1
	1.5 (0.2–5.3)	2.5 (0.1–14.0)	1.7 (0.4–5.0)	3.5 (0.7–10.3)	— (0.0–124.2)	3.4 (0.7–10.0)	2.3 (0.7–5.3)	2.3 (0.1–13.1)	2.3 (0.8–4.9)	0.7 (0.0–3.8)
Other bacterial diseases (ICD 030–041)	39	19	58	13	2	15	52	21	73	46
	2.0 (1.4–2.8)	1.6 (1.0–2.5)	1.9 (1.4–2.4)^*	1.3 (0.7–2.3)	2.5 (0.3–9.2)	1.4 (0.8–2.4)	1.8 (1.3–2.3)^*	1.7 (1.0–2.6)^*	1.8 (1.4–2.2)^*	1.6 (1.1–2.1)^*
Diabetes (ICD 250)	69	29	98	37	1	38	106	30	136	76
	1.3 (1.0–1.6)	1.0 (0.7–1.5)	1.2 (1.0–1.5)	1.4 (1.0–1.9)	0.4 (0.0–2.1)	1.3 (0.9–1.8)	1.3 (1.1–1.6)^*	1.0 (0.7–1.4)	1.2 (1.0–1.4)^*	0.9 (0.7–1.2)
Meningitis (ICD 320–322)	3	2	5	0	0	0	3	2	5	1
	3.9 (0.8–11.5)	2.5 (0.3–9.1)	3.2 (1.0–7.5)^*	— (0.0–14.3)	— (0.0–105.4)	— (0.0–12.6)	2.9 (0.6–8.6)	2.4 (0.3–8.7)	2.7 (0.9–6.3)	0.7 (0.0–3.9)
Intracranial and intraspinal abscess (ICD 324)	1	1	2	2	0	2	3	1	4	0
	2.8 (0.1–15.7)	4.2 (0.1–23.1)	3.4 (0.4–12.1)	23.7 (2.9–85.7)^*	— (0.0–494.5)	21.8 (2.6–78.7)^*	6.8 (1.4–20.0)^*	4.0 (0.1–22.4)	5.8 (1.6–14.9)^*	— (0.0–8.2)
Acute rheumatic fever (ICD 390–392)	0	2	2	0	0	0	0	2	2	0
	— (0.0–17.8)	20.4 (2.5–73.8)^*	6.5 (0.8–23.7)	— (0.0–44.2)	— (0.0–781.6)	— (0.0–41.8)	— (0.0–12.7)	19.5 (2.4–70.5)^*	5.1 (0.6–18.4)	— (0.0–16.7)
Ischemic heart disease (ICD 410–414)	860	174	1,034	218	12	230	1078	186	1264	588
	1.1 (1.0–1.2)^*	0.8 (0.7–1.0)^*	1.1 (1.0–1.1)	1.0 (0.9–1.1)	1.2 (0.6–2.0)	1.0 (0.9–1.2)	1.1 (1.0–1.2)^*	0.8 (0.7–1.0)^*	1.0 (1.0–1.1)	1.0 (0.9–1.1)
Functional diseases of the heart (ICD 426, 427)	29	19	48	21	2	23	50	21	71	51
	0.6 (0.4–0.8)^*	0.8 (0.5–1.3)	0.7 (0.5–0.9)^*	0.9 (0.6–1.4)	1.5 (0.2–5.3)	0.9 (0.6–1.4)	0.7 (0.5–0.9)^*	0.9 (0.5–1.3)	0.7 (0.6–0.9)^*	0.8 (0.6–1.1)
Subarachnoid hemorrhage (ICD 430)	10	7	17	4	0	4	14	7	21	8
	1.3 (0.6–2.3)	1.8 (0.7–3.6)	1.4 (0.8–2.3)	0.7 (0.2–1.9)	— (0.0–9.1)	0.7 (0.2–1.8)	1.0 (0.6–1.8)	1.6 (0.6–3.3)	1.2 (0.7–1.8)	0.6 (0.3–1.2)
Occlusion/stenosis precerebral & cerebral arteries (ICD 433, 434)	31	4	35	17	0	17	48	4	52	53
	0.4 (0.3–0.6)^*	0.1 (0.0–0.4)^*	0.4 (0.3–0.5)^*	0.4 (0.2–0.6)^*	— (0.0–1.6)	0.4 (0.2–0.6)^*	0.4 (0.3–0.6)^*	0.1 (0.0–0.3)^*	0.4 (0.3–0.5)^*	0.6 (0.4–0.8)^*
Aortic aneurysm (ICD 441)	20	7	27	10	2	12	30	9	39	14
	0.8 (0.5–1.2)	1.4 (0.6–2.9)	0.9 (0.6–1.3)	1.9 (0.9–3.6)	9.0 (1.1–32.5)^*	2.2 (1.2–3.9)^*	1.0 (0.7–1.4)	1.7 (0.8–3.2)	1.1 (0.8–1.5)	0.9 (0.5–1.6)
Abscess of lung (ICD 513)	2	0	2	1	0	1	3	0	3	7
	0.3 (0.0–1.1)	— (0.0–1.6)	0.2 (0.0–0.8)^*	0.5 (0.0–2.8)	— (0.0–39.2)	0.5 (0.0–2.6)	0.3 (0.1–1.0)	— (0.0–1.5)	0.3 (0.1–0.8)^*	1.3 (0.5–2.6)
Cirrhosis of liver (ICD 571–573)	74	20	94	9	1	10	83	21	104	62
	1.3 (1.0–1.6)^*	0.8 (0.5–1.2)	1.1 (0.9–1.4)	0.6 (0.3–1.2)	1.0 (0.0–5.4)	0.7 (0.3–1.2)	1.2 (0.9–1.4)	0.8 (0.5–1.2)	1.1 (0.9–1.3)	1.1 (0.8–1.4)
Chronic nephritis (ICD 582)	6	2	8	5	0	5	11	2	13	11@
	1.9 (0.7–4.1)	0.6 (0.1–2.2)	1.2 (0.5–2.5)	5.3 (1.7–12.3)^*	— (0.0–22.6)	4.5 (1.5–10.5)^*	2.7 (1.3–4.8)^*	0.6 (0.1–2.1)	1.7 (0.9–2.9)	2.0 (1.0–3.6)^*
Other diseases of kidney and ureter (ICD 593)	7	6	13	3	0	3	10	6	16	11
	2.3 (0.9–4.8)	2.1 (0.8–4.6)	2.2 (1.2–3.8)^*	2.8 (0.6–8.3)	— (0.0–20.4)	2.4 (0.5–7.1)	2.5 (1.2–4.6)^*	2.0 (0.7–4.3)	2.3 (1.3–3.7)^*	2.0 (1.0–3.5)
Transport accidents (ICD E800–E829)	4	0	4	1	0	1	5	0	5	2
	0.1 (0.0–0.2)^*	— (0.0–0.2)^*	0.1 (0.0–0.1)^*	0.1 (0.0–0.6)^*	— (0.0–7.8)	0.1 (0.0–0.6)^*	0.1 (0.0–0.2)^*	— (0.0–0.2)^*	0.1 (0.0–0.1)^*	0.0 (0.0–0.1)^*
Accidental falls (ICD E880–E888)	4	1	5	1	0	1	5	1	6	2
	0.2 (0.1–0.6)^*	0.2–(0.0–0.9)^*	0.2 (0.1–0.5)^*	0.2 (0.0–0.9)^*	— (0.0–22.2)	0.2 (0.0–0.9)^*	0.2 (0.1–0.5)^*	0.2 (0.0–0.9)^*	0.2 (0.1–0.4)^*	0.1 (0.0–0.5)^*
Other accidents (ICD E900–E928)	4	0	4	0	0	0	4	0	4	4
	0.1 (0.0–0.4)^*	— (0.0–0.3)^*	0.1 (0.0–0.2)^*	— (0.0–0.8)^*	— (0.0–12.2)	— (0.0–0.7)^*	0.1 (0.0–0.3)^*	— (0.0–0.2)^*	0.1 (0.0–0.2)^*	0.1 (0.0–0.4)^*
Suicide & self-inflicted injury (ICD E950–E959)	2	0	2	0	0	0	2	0	2	0
	— (0.0–0.2)^*	— (0.0–0.5)^*	— (0.0–0.1)^*	— (0.0–0.6)^*	— (0.0–26.3)	— (0.0–0.6)^*	— (0.0–0.1)^*	— (0.0–0.5)^*	— (0.0–0.1)^*	— (0.0–0.1)^*
All causes	3,197	1,011	4,208	1,095	56	1,151	4,292	1,067	5359	3071
	1.2 (1.1–1.2)^*	1.0 (0.9–1.0)	1.1 (1.1–1.2)^*	1.1 (1.1–1.2)^*	1.1 (0.8–1.4)	1.1 (1.1–1.2)^*	1.2 (1.1–1.2)^*	1.0 (0.9–1.0)	1.1 (1.1–1.2)^*	1.1 (1.1–1.2)^*

Statistically significant at the 95% confidence level and figures in parentheses are confidence intervals @ 10 of the 11 deaths occurred in three soup canning plants, and one in an oyster shucking plant.

In the table, causes of death that were significantly in excess in the cohort include the following: other bacterial diseases (ICD 030-041), SMR = 1.8 (95% CI 1.4–2.2)—all the deaths were due to septicemia (ICD 038); diabetes, SMR = 1.2 (95% CI 1.0–1.4); intracranial and intraspinal abscess, SMR = 5.8 (95% CI 1.6–14.9); other diseases of kidney and ureter, SMR = 2.3 (95% CI 1.3–3.7); and all causes of death, SMR = 1.1 (95% CI 1.1–1.2).

Significantly elevated SMRs that were confined to particular subgroups include that for meningitis in males (SMR = 3.2, 95% CI 1.0–7.5); acute rheumatic fever in nonwhite males (SMR = 20.4, 95% CI 2.5–73.8); ischemic heart disease in white males (SMR = 1.1 (95% CI 1.0–1.2); aortic aneurysm in nonwhite females (SMR = 9.0 (1.1–32.5); cirrhosis of the liver in white males (SMR = 1.3, 95% CI 1.0–1.6); and chronic nephritis in white females (SMR = 5.3, 95% CI 1.7–12.3).

Though not shown in the table, there was a 3.8-fold significant risk of diseases of the pancreas in white males in processing plants.

The risks for intestinal infectious diseases (e.g., E. coli infection, salmonellosis, shigellosis, typhoid, and paratyphoid) were elevated in nearly all subgroups but were not statistically significant.

Causes of death for which a significantly depressed SMR was observed in the entire cohort or in a subgroup include deaths from various accidents; suicide and self-inflicted injury; functional diseases of the heart; and occlusion/stenosis of the precerebral and cerebral arteries, and abscess of the lung.

Discussion

Other investigators have studied mortality in meat workers before, but only few examined noncancer mortality (Guberan et al. 1993, Coggon and Wield 1995), and data were presented on only a few causes of death defined mostly by systems or broad groups (circulatory system, endocrine and metabolic systems, genito-urinary system, nervous system, circulatory disease, etc.). This report is important because we studied over 135 separate individual causes of death from nonmalignant diseases, which to date is the only study that has examined more than 60 causes of death.

In our prior studies of this cohort excess risk of death was observed for septicemia, chronic nephritis, other diseases of kidney and ureter, cirrhosis of the liver, ischemic heart disease, acute and subacute endocarditis, and functional diseases of the heart (conduction disorders and cardiac dysrhythmias) (Johnson 1987a, Johnson et al. 2007). These conditions continue to be in excess in this update. In the current report we identified new causes of death not previously reported that are now observed to be in excess. These include intracranial and intraspinal abscess, meningitis, acute rheumatic fever, aortic aneurysm, diseases of the pancreas, and diabetes. Thus, all these conditions represent in total the causes of death that would likely be associated with long-term effects of food animal transmissible agents if at all these agents cause long-term disease in humans.

Although not shown, analysis revealed that the overwhelming majority of deaths from these conditions occurred after 20 years since the date of start of employment, indicating that either these conditions persist for a long time before death occurs, or that these infections do not occur easily and that long durations of employment at high exposures are required for them to occur. The findings for the meat workers appear to be specific for the group, as they were different from those obtained for nonmeat workers from the same union, and from the U.S. population. The occurrence of chronic nephritis and other bacterial disease (mostly septicemia) in nonmeat workers is not unexpected, as many of them worked in oyster shucking, and oyster and meat soup canning, and industries that involve exposure to infectious agents also. We do not have an explanation for the observed decreased risk of precerebral and cerebral artery stenosis in both groups.

The cohort exhibited excess of deaths as expected from conditions known to be associated with infections such as septicemia, meningitis, kidney diseases, intracranial and intraspinal abscess, diseases of the pancreas, liver cirrhosis, aortic aneurysm, and acute rheumatic fever. Importantly, for successful treatment, clinicians should consider the possible zoonotic origin in treating cases of these conditions in workers and in the general population, and in selecting appropriate antibiotics that are not resistant to some of these organisms, as there is a history of intense antibiotics use in these animals (Gilchrist et al. 2006).

It is interesting that there was an observed excess of conditions such as ischemic heart disease, functional diseases of the heart, and diabetes that are not known to have an established infectious etiology. This raises the possibility no matter how remote that these conditions could be related to infections.

With regards to diabetes, an infective origin has been suggested before (Porte et al. 2003), and this may be consistent with the increase in deaths from diseases of the pancreas in white males. However, it is also well established that individuals with diabetes are highly prone to severe infections, in this case infections being the result rather than the cause of diabetes (Bertoni et al. 2001). This would indicate that the observed increased risk of death from diabetes in this study is a result of increased occurrence of severe infections in those with diabetes.

Similarly for ischemic heart disease, there is evidence that atherosclerosis is associated with certain microbial agents such as chlamydia, helicobacter pylori, and cytomegalovirus, and already in clinical trials some success has been achieved with treating coronary artery disease with antibiotics (Gurfinkel and Bozovich 1999, Hodinka 1999, Kusters and Kuipers 1999, Anderson et al. 2004). It should be noted also that atherosclerosis has been experimentally induced in chickens with Marek's disease virus, a herpes virus that commonly infects chickens (Fabricant and Fabricant 1999). Thus, it is not implausible to entertain the possibility that these major chronic diseases in humans could be related to zoonotic infections from food animals.

Since the study is the first to present this level of detail on nonmalignant conditions in workers exposed to zoonotic infectious agents, the results should be regarded as preliminary until confirmed by others, as they could be due to chance, resulting from multiple comparisons. Because of this, a more stringent application of the level of statistical significance to interpret preliminary results such as use of Bonferroni correction is not warranted at this time. Also, a more thorough assessment of any proposed risk could have been discussed with consideration of life course theory in the occurrence of chronic conditions. However, the type of data available for the analysis was limited to demographic variables and department worked in, contained in union records. This is clearly not sufficient to address the complex issues involved in using a life course approach (Ben-Shlomo and Kuh 2002).

The initial purpose of this study was simply to answer the question whether workers who have high exposures to these agents show evidence of excess occurrence of known infectious and other diseases. This study has confirmed that they do. The next step is to conduct rigorous studies aimed at determining the following: (1) whether the excess of these diseases results from infection transmission within the workplace; (2) if so, whether these diseases are truly zoonotic and are caused by agents originating from the animals; (3) or whether the excess occurrence simply reflects an increased transmission among workers within a highly confined workplace, of microbial agents that normally originate and cause these diseases in human populations.

The conduct of appropriate epidemiologic nested case–control studies with detailed information collected on occupational and nonoccupational exposures, complemented with laboratory-based studies of infection such as serological and molecular studies will assist in answering these questions and in identifying the agents responsible.

Limitations of the study include the unavailability of incidence data on the occurrence of these conditions. For example, the absence of data on time of first infection or onset of disease precludes knowing whether the deaths from the conditions reported here occurred 20 years since the initial date of hire, is due to a long incubation period before disease or death occurs, or is because a protracted duration of exposure is needed before disease occurs. The absence of data on specific organisms is also a limitation.

Since duration of employment was not updated after the first follow-up of the cohort, analysis by duration of exposure was not possible. This might not be a serious setback in all instances, when one is dealing with infectious agents, for the following reasons: (1) a long duration of exposure is not absolutely needed to cause severe disease or death, since a single one-time heavy dose of infection can be equally lethal; (2) some organisms elicit a strong protective immunity in the host that can be life-long, while others elicit transient or weak immune response that may convey no protection to the host, thus making repeated infections possible; (3) for some organisms, the effects of vaccination may be important. These factors in some cases might complicate the manifestation of disease outcome and make it difficult to elicit clear-cut duration of exposure/outcome relationships when one is dealing with infectious agents.

Conclusion

High exposure to transmissible agents present in food animals and their products may be associated with excess mortality from conditions known to be associated with infections. The observed association with ischemic heart disease and diabetes is interesting and consistent with efforts linking atherosclerosis and coronary heart disease with infections, and may point to a new role for agents present in food animals and their products in their etiology, and therefore needs further investigation.

Footnotes

Acknowledgments

This study was funded by a grant (1 RO1 OH008687) from the National Institute for Occupational Safety and Health. Other than providing the funds, the agency had no involvement in the design, collection, analysis, and interpretation of the data. We wish to thank the United Food and Commercial Workers' International and local unions for their support, without which this study would not have been possible. We wish to thank Will Anthony, Harry McCraney, and Richard Tatum II, for their assistance in proof reading various drafts of the article.

This study was approved by the University of North Texas Health Sciences Center Institutional Review Board for Human Subjects Research. All procedures performed were in accordance with the ethical standards of the Institutional Research Committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

Author Disclosure Statement

No competing financial interests exist.

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