Transversal Descriptive Study of Xenobiotic

Cara Yvonne Jeppe, Martin Derrick Smith
Department of Surgery, Chris Hani Baragwanath Hospital, Gauteng Department of Health.
Johannesburg, Republic of South Africa
Dear Sir:
There have been a substantial number of
reports in the literature linking pancreatitis
and pancreatic cancer to certain xenobiotics
and occupations. It has been hypothesized that
exposure to volatile hydrocarbons and
particularly
petrochemicals
increases
susceptibility to pancreatitis. We performed a
study aimed to enumerate occupational and
environmental xenobiotics described in the
literature as potential risk factors for
pancreatitis and to document exposures to
these in chronic pancreatitis patients
presenting with chronic pain for surgery.
In their editorial on a life course approach to
chronic disease epidemiology Ben-Shlomo
and Kuh state “Life course epidemiology has
challenged the complacency of the adult
lifestyle model of chronic disease risk. It has
particularly acted as a catalyst for new
research in the area of social inequalities in
health and has helped bridge biological,
psychological and social models of disease
causation.” The approach they say is
intuitively obvious but empirically complex
[1].
Chronic pancreatitis is an aggressive and
progressive disease, usually presenting with
abdominal pain although the condition may
be painless. Progression includes inflam-
matory fibrosis, patchy acinar atrophy,
intraductal calcium carbonate stones, and an
increased risk of diabetes, malabsorption and
pancreatic cancer.
Long-term alcohol abuse and smoking have
been cited as the major causes of chronic
pancreatitis with reduced intakes of anti-
oxidants being a compounding factor. Less
common causes in the South African
environment include gallstones, drugs,
infections, trauma, ischemia and genetic
factors. Where alcohol is not implicated and
there is no record of another recognized
etiological agent the disease is generally
classified idiopathic. In 1986 Braganza et al.
suggested that “occupational exposure to
aromatic or chlorinated hydrocarbons may be
relevant not only in idiopathic pancreatitis
but also in alcohol-related pancreatic
disease”. They supported the suggestion with
evidence of recurrent symptoms after re-
exposure to volatile chemicals despite
abstinence from alcohol [2].
Causal associations between a number of
occupational and environmental xenobiotics
and pancreatitis have been suggested, most of
which have been found in manual workers. A
multicenter historical cohort study found “The
risk of pancreatic cancer is significantly
elevated in subjects with chronic pancreatitis
and appears to be independent of sex, country
and type of pancreatitis” [3]. According to
Longnecker “Epidemiological studies indicate
that chemical carcinogenesis is the cause of
the increasing US exocrine cancer incidence
[4].
In August 1999 a website CCINFO (http://
ccinfoweb.ccohs.ca/) search was conducted in
the NIOSHTIC
®
(http://www.ccohs.ca/

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236
products/databases/nioshtic.html) and OSHLINE
®
(http://www.ccohs.ca/products/databases/
oshline.html) databases, in order to identify
industries, occupations and xenobiotics
suggested to be associated with pancreatitis
and pancreatic cancer in humans. The
databases are produced by the US National
Institute for Occupational Safety and Health
Table 1. Risk industries and hazardous agents defined by the CCINFO (http://ccinfoweb.ccohs.ca/) database, and
numbers of patients employed in each industry.
Industry
Agent
No.
Acetylene production (welding)
8
Agriculture
Anticholinesterase, organophosphate, organochlorine insecticides
(parathion, demeton, sulfotep, trichlorphon, dimethoate, dichlorphos,
methylparathion, methamidophos, omethoate), pesticides and weed
killers
6
Automobile engine and parts
manufacture, service and maintenance
Gasoline and diesel fumes, deletion fluids
12
Brick and stone masonry
Limestone, marble, mica, cement, quartz (crystalline dust), silica dust 0
Catering, cooking and serving
Grain dust, starch, sucrose
8
Dispensing
Benzene, toluene, ethyl benzene, xylene
1
Dry cleaning
Benzene
1
Engine factories and machine operations
Dimethylformamide solvent
15
Gasoline production
Benzene, toluene, ethyl benzene, xylene (skin contact, accidental
ingestion and vapor inhalation)
0
Glue manufacture
Glue based on organic solvents
0
Handling of cancer chemotherapeutics
0
Horticulture
Anticholinesterase, organophosphate and organochlorine insecticides,
pesticides and weedkillers
12
Jewelry making
Dichloracetylene
1
Leather tanning
1
Lithography and printing
Aniline dyes, paints and lacquers, (xylene, light petroleum spirit,
thinner, ethanol, acetone, ethyl-butyl-acetate, isoproponol), organic
chlorinated solvents (white spirit, 20% aromatic/80% aliphatic
hydrocarbons)
13
Metallurgy
Aluminum
2
Oil refining
0
Painting
Paints and lacquers, organic chlorinated solvents, turpentine
29
Petrochemical industry
Gasoline, benzidine, beta naphthylamine, vinyl chloride/acetate/bromide 1
Photoengraving
3
Reinforced plastics
Styrene, vinyl chloride, polyvinyl chloride
1
Research and chemical laboratories
Warfarin, toluene
0
Rubber industry
Rubber fume and process dust
1
Sheet metal manufacture
0
Steel milling
Aluminum, coal tar pitch derivatives
2
Textiles
0
Transport industry
16
Wood furniture manufacture
Pentachlorophenol, wood preservatives and lacquers
9

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237
and the Canadian Centre for Occupational
Health and Safety (CCOHS). A table of
control limits for hazardous chemical
substances under the Occupational Health and
Safety Act 85 (OHSA) of 1993
(http://www.info.gov.za/acts/1993/a85-93.pdf)
was obtained from the South African
Department of Labour.
Approval for the study was obtained from the
Human Research Ethics Committee (Medical)
of the University of the Witwatersrand,
protocol number M050425.
All consecutive patients with chronic
pancreatitis presenting for surgery at the
Hepatopancreaticobiliary Units of the JG
Strijdom/Helen Joseph Hospital in Auckland
Park and the Chris Hani Baragwanath
Hospital in Soweto, Johannesburg, South
Africa between January 1991 and January
2006 answered a questionnaire after verbal or
written consent was obtained. Their condition
was diagnosed at endoscopic retrograde
cholangiopancreatography and computed
tomography scan, and, in the majority,
confirmed at surgery with histopathology.
The interviews were conducted by a single
interviewer not engaged in treatment
decisions. Questions relating to lifetime
employment, occupations, exposure to
commonly occurring xenobiotics, clinical
details and psychosocial circumstances were
included in the questionnaire. Self-reports of
exposure to specific xenobiotics were
obtained where possible and exposures to
broad categories of agents (e.g. solvents,
insecticides) were obtained when the
chemical names of hazardous substances were
unknown. Employers’ records were not
sought as most jobs occurred prior to the
study, many patients had been
temporary/contract and self-employed workers,
and many had been unregistered or employed
in the informal sector. It was therefore not
possible to ascertain exposure levels.
Twenty-nine industries and more than 40
xenobiotics linked to pancreatitis in the
literature were identified in the database
search (Table 1). All these xenobiotics were
identified as hazardous chemical substances
in the OHSA list.
One-hundred and 12 patients answered the
questionnaire, of which 14 were female.
There was one patient that declined and was
excluded. The mean (±SD) age of patients
was 44.4±8.7 years. Ten patients were found
at surgery to have pancreatic cancer and one
developed it some time after a duodenal
preserving resection of the pancreas and
lateral
pancreaticojejunostomy
(Frey
procedure). Since pancreatic cancer can
develop many years after the onset of chronic
pancreatitis when patients may be lost to
follow-up, these eleven cancer cases do not
reflect the incidence of progression to cancer
in this population of chronic pancreatitis
patients.
Eighty-two (73.2%) of 112 patients had been
employed in enumerated industries: 39
(34.8%) in one, 31 (27.7%) in two, 9 (8.0%)
in three, and 3 (2.7%) in four. Forty-three
(38.4%) had been employed in the
automobile, engine and parts manufacture,
maintenance and service, engine factories and
machine operations, and the transport
industries; 29 (25.9%) in the painting
industry; 18 (16.1%) in agriculture and
horticulture; 16 (14.3%) in the lithography
and printing, and photoengraving industries,
and 9 (8.0%) in wood furniture manufacture.
There were between one and eight of the
patients employed in each of the acetylene
production, dispensing, dry cleaning, jewelry
making, leather tanning, metallurgy,
petrochemical, reinforced plastics, rubber, and
steel milling industries (Table 1).
Apart from the high proportion of alcohol
consumers and smokers, 11 (9.8%) of patients
had been exposed to various solvents: 15
(13.4%) to benzene; 18 (16.1%) to herbicides,
pesticides, insecticides; 20 (17.9%) to diesel;
21 (18.8%) to petrol; 33 (29.5%) to
turpentine; 58 (51.8%) to thinners; 66
(58.9%) to paraffin; 67 (59.8%) to paint,
lacquer, varnish; 86 (76.8%) to burning
firewood and coal (Table 2).
Before surgery 71 (63.4%) expressed an
inability to continue manual work as a result
of their illness and 44 (39.3%) had been
retrenched. Forty-three had diabetes (38.4%)
of whom 29 (25.9%) were insulin dependent,

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238
53 (47.3%) had steatorrhea, 96 (85.7%) loss
of weight, and 57 (50.9%) expressed
hopelessness prior to their surgery.
Chronic pancreatitis has been described as
endemic in the township of Soweto [5] where
exposure to environmental xenobiotics such
as burning firewood and coal, and paraffin
used in Primus stoves has historically been
universal. Differentiation between occupational
and confounding environmental agents would
require comparison with a population of
patients employed in “risk” occupations but
not having been exposed to these
environmental agents. In South Africa such a
population does not yet exist. Furthermore
since exposures may occur many years before
the onset of chronic pancreatitis, and may be
multifactorial but not continuous, such
differentiation is impracticable.
In South Africa many patients are treated
empirically for epigastric pain, presumed to
be due to peptic ulcer disease. Consequently
the diagnosis of chronic pancreatitis tends to
be made at advanced stages of the disease.
Diagnostic investigations such as magnetic
resonance and endoscopic retrograde
cholangiopancreatography, and computed
tomography scan are not appropriate
screening tools due to limited resources in
many public health facilities, high costs, and
their invasive nature. Thus exclusion of
chronic pancreatitis in controls with these
methods is neither practicable nor ethically
acceptable.
In their case-referent study McNamee et al.
identified “close exposure to volatile
hydrocarbons, especially petrochemicals, as
an independent risk factor in chronic
pancreatitis” [6]. They attributed treatment
failure partially to daily close exposure to
occupational chemicals. Abstinence from
alcohol would not therefore provide
protection from further episodes of acute on
chronic pancreatitis and progression of the
disease to irreversible pancreatic insufficiency
in those who continue to be exposed to such
chemicals. Such evidence requires that
diagnosticians routinely investigate life
course exposures to volatile hydrocarbons.
In the study presented here, that was primarily
designed to assess the effectiveness of pain-
relieving surgery for chronic pancreatitis,
enthusiasm for the life course approach was
frustrated by a number of obstacles that
resulted in methodological weaknesses. No
exposure levels for specific agents were
obtainable as most patients were unable to
identify them in poorly defined job categories
with inadequate health and safety
information. Individual exposure levels were
also unavailable as employment records have
been rare for manual workers and industry
compliance with occupational health and
safety controls has been traditionally poor.
Therefore no attempt was made to access this
information.
No dose-effect relationship could be
determined in the study and thus only a
suggested relationship between exposure and
disease is postulated. The fact that the
cumulation of exposures to occupational and
environmental xenobiotics in this working
class population of patients may reduce the
effectiveness of preventive interventions
Table 2. Percentage of xenobiotic exposure in 112
pancreatitis patients.
Agent
Cases
Alcohol
- Special occasions
- Weekends only
- Daily
- Alcoholics
104 (92.9%)
6 (5.4%)
49 (43.8%)
44 (39.3%)
5 (4.5%)
Cigarettes
- Less than 5/day
- 5-10/day
- 11-20/day
>20/day
90 (80.3%)
29 (25.9%)
28 (25.0%)
23 (20.5%)
10 (8.9%)
Various solvents
11 (9.8%)
Benzene
15 (13.4%)
Herbicides, pesticides, insecticides
18 (16.1%)
Diesel
20 (17.9%)
Petrol
21 (18.8%)
Turpentine
33 (29.5%)
Thinners
58 (51.8%)
Paraffin
66 (58.9%)
Paint, lacquer, varnish
67 (59.8%)
Burning firewood and coal
86 (76.8%)

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JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 9, No. 2 - March 2008. [ISSN 1590-8577]
239
(such as electrification of homes and
improved compliance with workplace health
and safety regulations) does not diminish the
need for prevention. Joint exposure to a
number of “risk” factors may not be
interactive in which case the relative “risks”
become multiplicative. Stringent measures to
reduce “risk” exposure should be
implemented to curtail the widespread
incidence of a disease with such poor
prognosis and grave personal and social
consequences.
This audit suggests that people exposed to
certain xenobiotics can develop chronic
pancreatitis. However these particular agents
will need to be tested in a future case-control
study.
Received July 4
th
, 2007 - Accepted December
12
th
, 2007
Keywords Diabetes Mellitus; Malabsorption
Syndromes;
Pancreatic
Neoplasms;
Pancreatitis; Xenobiotics
Conflict of interest The authors have no
potential conflicts of interest
Correspondence
Cara Jeppe
Department of Surgery
2
nd
Floor, Friends of Baragwanath Building
Chris Hani Baragwanath Hospital
P.O. Bertsham
2013 Republic of South Africa
 
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