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Elevated urinary levels of kidney injury molecule-1 among Chinese factory workers
exposed to trichloroethylene
Roel Vermeulen1,*, Luoping Zhang2, Annejet
Spierenburg1, Xiaojian Tang3, Joseph V Bonventre4, Boris
Reiss1, Min Shen5, Martyn T. Smith2, Chuangyi Qiu3,
Yichen Ge3, Zhiying Ji2, Jun Xiong6, Jian He7, Zhenyue
Hao8, Songwang Liu9, Yuxuan Xie3, Fei Yue3, Weihong
Guo2, Mark Purdue5, Laura E. Beane Freeman5, Venkata
Sabbisetti4, Laiyu Li3, Hanlin Huang3,†, Nathaniel
Rothman5,† and Qing Lan5,†
1Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The
Netherlands 2School of Public Health, University of California, Berkeley, CA,
USA 3Guangdong Poison Control Center, Guangdong, P. R. China 4 Renal
Division, Department of Medicine, Brigham and Women’s Hospital, Harvard
Medical School, Boston, MA 02115, USA 5Division of Cancer Epidemiology
and Genetics, National Cancer Institute, Bethesda, MD, USA 6Dongguan Center
for Disease Control and Prevention, Guangdong, P. R. China 7Zhongshan Center
for Disease Control and Prevention, Guangdong, P. R. China 8Institute for
Breast Cancer Research and University Health Network, Toronto, ON, Canada
9Qiaotou Hospital, Dongguan, Guangdong, P. R. China
*To whom correspondence should be addressed. Environmental
Epidemiology Division, Institute for Risk Assessment Sciences, Utrecht
University, Jenalaan 18D, 3584 CK Utrecht, The Netherlands. Tel: +31 30
253 9448; Fax: +31 30 253 9449; Email: R.C.H.Vermeulen@uu.nl
Epidemiological studies suggest that trichloroethylene (TCE)
exposure may be associated with renal cancer. The biological
mechanisms involved are not exactly known although nephro-
toxicity is believed to play a role. Studies on TCE nephrotoxic-
ity among humans, however, have been largely inconsistent. We
studied kidney toxicity in Chinese factory workers exposed to
TCE using novel sensitive nephrotoxicity markers. Eighty healthy
workers exposed to TCE and 45 comparable unexposed controls
were included in the present analyses. Personal TCE exposure
measurements were taken over a 2-week period before urine col-
lection. Ninety-six percent of workers were exposed to TCE below
the current US Occupational Safety and Health Administration
permissible exposure limit (100 ppm 8 h TWA), with a mean
(SD) of 22.2 (35.9) ppm. Kidney injury molecule-1 (KIM-1) and
Pi-glutathione S transferase (GST) alpha were elevated among
the exposed subjects as compared with the unexposed controls
with a strong exposure-response association between individual
estimates of TCE exposure and KIM-1 (P < 0.0001). This is the
first report to use a set of sensitive nephrotoxicity markers to
study the possible effects of TCE on the kidneys. The findings
suggest that at relatively low occupational exposure levels a toxic
effect on the kidneys can be observed. This finding supports the
biological plausibility of linking TCE exposure and renal cancer.
Trichloroethylene (TCE) is a volatile chlorinated organic compound
commonly used in industrial settings as a degreaser for metal parts
and general-purpose solvent for lipophilic compounds. In 1995, it was
estimated that more than 400 000 workers were exposed to TCE on an
annual basis in the United States (1). Further, as a consequence of its
presence in workplaces for many years and relative stability, TCE has
become a widespread environmental water contaminant and one of
the most frequently observed chemicals at Superfund sites.
TCE has recently been classified by the US EPA as carcinogenic in
humans by all routes of exposure, whereas the National Toxicology
Program classified TCE as reasonably anticipated to be a human car-
cinogen based on limited evidence of carcinogenicity from studies in
humans, and sufficient evidence of carcinogenicity from studies in
experimental animals and information suggesting TCE acts through
mechanisms that indicate it would probably cause cancer in humans
(2,3). Evidence for the carcinogenicity of TCE in humans is strong-
est for liver and kidney cancers and non-Hodgkin’s lymphoma (4).
A recent meta-analysis of 23 studies on kidney carcinogenicity of
TCE in humans showed a probable relationship between TCE expos-
ure and kidney cancer (5). TCE is bioactivated to reactive intermedi-
ates through the renal glutathione S transferase (GST) and cysteine
conjugate beta-lyase enzymes to form cysteine S conjugates, which
are believed to be responsible for its nephrotoxic and nephrocarcino-
genic effects (6,7). Therefore, the recent findings of an increased risk
among TCE-exposed subjects especially in those subjects carrying
polymorphisms in GST and cysteine conjugate beta-lyase genes has
provided strong biological plausibility of an association between TCE
and renal cancer in humans (7).
Long-term animal studies have shown low incidences of renal aden-
oma and adenocarcinoma in a number of rat strains (8). Rats given
TCE orally or by inhalation also developed non-neoplastic lesions in
the kidneys at relatively low dose levels. It has been suggested that
kidney tumours in rats arise as a result of persistent cytotoxicity and
regeneration. However, although nephrotoxicity occurs also in mice
they do not seem to develop renal neoplasms. As such, kidney tox-
icity seems to be a possible but insufficient contributing factor for
rodent renal carcinogenesis. It is worthy to note that mutagenicity has
been proposed to contribute, independently of cytotoxicity and regen-
eration, to renal tumorigenesis in the rat (7). Data from human studies
on TCE and nephrotoxicity are limited but have suggested that there
might be a toxic effect of TCE on the kidneys at relatively high expos-
ure levels (>35 ppm) (9–12). Information on nephrotoxicity at lower
TCE doses is generally lacking.
Recently, several new sensitive markers of kidney toxicity have been
developed including glutathione S transferase alpha and pi (Alpha-
GST and Pi-GST) and kidney injury molecule-1 (KIM-1), which
enables the identification of low level kidney toxicity. To address ques-
tions about TCE’s potential to cause kidney cancer, we carried out a
cross-sectional study to evaluate the impact of occupational expos-
ure to TCE on kidney injury using a panel of nephrotoxicity markers
(i.e. Alpha- and Pi-GST, KIM-1, vascular endothelial growth factor
(VEGF), N-acetyl-beta-(d)-glucosaminidase (NAG) activity).
To select factories for study, we conducted an initial screening of more than
40 potential study factories over a 1 year period using Dräger tubes and 3M
organic vapour monitoring (OVM) badges to measure TCE and other chemi-
cals including benzene, styrene, ethylene oxide, formaldehyde, methylene
chloride, chloroform, perchloroethylene and epichlorohydrin. Factories were
included if they used TCE in manufacturing processes, had no detectable ben-
zene, styrene, ethylene oxide, formaldehyde or epichlorohydrin levels, and low
to negligible levels of methylene chloride, chloroform or perchloroethylene.
Ultimately, six study factories with metal (n = 4), optical lenses (n = 1) and
circuit boards (n = 1) cleaning processes were identified that fulfilled the above
selection criteria (13).
In June and July, 2006, we carried out a cross-sectional study of 80 work-
ers currently exposed to TCE in the six study factories with TCE cleaning
operations and 45 unexposed controls. Control subjects were enrolled from
a clothing manufacturing factory and a food production factory that did not
Abbreviations: GST, glutathione-S-transferase; KIM-1, kidney injury
molecule-1; NAG, N-acetyl-beta-(d)-glucosaminidase; OVM, organic vapour
monitoring; TCE, trichloroethylene; VEGF, vascular endothelial growth factor.
Carcinogenesis vol.33 no.8 pp.1538–1541, 2012
Advance Access Publication June 4, 2012
at University of California, Berkeley on September 1, 2012
use TCE and were in the same geographic region as the factories that used
TCE. Controls were frequency matched by age (±5 years) to exposed work-
ers. Exclusion criteria for both TCE-exposed and unexposed workers included
history of cancer, chemotherapy and radiotherapy, as well as previous occu-
pations with notable exposure to benzene, butadiene, styrene and/or ionizing
radiation. The study was approved by Institutional Review Boards at the US
National Cancer Institute and the Guangdong National Poison Control Center,
China. Participation was voluntary and all subjects gave written informed
Exposure measurement and sample collection
For TCE-exposed workers (n = 80), full-shift personal air exposure measure-
ments, 2–3 per subject resulting in 235 measurements, were taken in a 2-week
time period in the factories using 3M OVM badges before biological sample
collection. For control workers (n = 45), a single OVM badge was collected
before biological sample collection. All OVM badges were analysed for TCE
by GC-MS (LOD 0.12 ppm) and a subset (48 from TCE-exposed workers)
was analysed for a panel of organic hydrocarbons including benzene (LOD
0.08 ppm), methylene chloride (LOD 0.14 ppm), perchloroethylene (LOD 0.1
ppm) and epichlorohydrin (LOD 0.1 ppm) by GC-MS. As part of the quality
control procedures, duplicate badges were analysed for TCE in Guangdong,
China and the United States and showed similar results with a Pearson cor-
relation of 0.99.
Subjects were interviewed using a questionnaire that requested information
about demographic and lifestyle characteristics and occupational history. They
were also asked to provide a peripheral blood, buccal cell mouth rinse and
urine samples, and undergo a brief physical exam that included measurement
of blood pressure, height, weight and temperature.
Post-shift urine samples were stored at 4°C until being processed within 10 h
of collection. Samples were centrifuged and 1.4 ml of urine supernatant was
then mixed with 0.3 ml freezing buffer (NEPHKIT® Urine Stabilizing Buffer;
Argutus Medical) to stabilize proteins for storage and freezing. Samples were
subsequently stored at −80°C.
Post-shift spot urine samples were analysed for creatinine, Alpha-GST,
Pi-GST, VEGF, KIM-1 and NAG concentrations. Creatinine was determined by
automated Jaffé reaction. Alpha-and Pi-GSTs were determined by a commer-
cially available ELISA kit (Argutus Medical). Urinary VEGF was determined
by commercially available ELISA kit (Quantikine Human VEGF Immunoassay;
R&D Systems). KIM-1 was determined by luminex-based XMAP technology
as described by Han et al. (14). Urinary NAG concentration was determined by
an enzyme substrate–based colorimetric assay. Assay CVs were 5% for Pi-GST,
10% for NAG, 15% for Alpha-GST and KIM-1, and 20% for VEGF.
Levels of TCE exposure and urinary markers were natural log transformed to
normalize their distributions. Student t-test was used to test for difference in
the natural logarithm (ln) of each endpoint between unexposed control and
exposed workers. In addition, exposure response analyses were performed by
linear regression. In these analyses, current TCE air levels in part per mil-
lion (ppm) were based on the arithmetic mean of an average of two to three
measurements per subject. Cumulative exposure in ppm years was calculated
by multiplying the individual arithmetic mean TCE levels with duration of
employment at the current job. Linear regression models included in addition
to the natural log–transformed exposure variables the frequency-matching fac-
tor age (as a continuous variable) and were corrected for ln(creatinine) (as a
continuous variable). In addition, potential confounders that have been shown
previously to influence one or more of the studied markers in this report were
included in a model for a given marker if the regression coefficient was altered
by ±15%, and included sex, current smoking (yes/no), current alcohol con-
sumption (yes/no) and body mass index (BMI). As current smoking and sex
were largely collinear (i.e. only men smoked) we only included sex in the final
models. All analyses were carried out using SAS version 9.2 software (SAS
Institute, Cary, NC, USA).
Demographic characteristics including age, sex, BMI, current smok-
ing and alcohol status were comparable between the unexposed con-
trol and exposed subjects (Table 1). Mean TCE exposure among the
exposed was 22 ppm (SD 35.9) while TCE exposure was negligible
in the control factories. On average, the exposed subjects worked for
2 years in the TCE facilities while unexposed subjects worked for
2.3 years in the control factories.
Urinary markers of kidney toxicity were comparable between the
unexposed and the exposed workers except for KIM-1, which was
statistically significantly elevated among the exposed subjects compared
with controls (t-test P = 0.01). Pi-GST was borderline statistically
significantly elevated among the exposed workers (t-test P = 0.09;
Table 2). Linear exposure-response modelling based on the natural
logarithm (Ln) of current and cumulative TCE exposure, corrected for
covariates [i.e. ln(creatinine), sex, current alcohol use and BMI], showed
significant associations with Ln(KIM-1) and borderline significant
associations with Ln(Pi-GST) (Table 3). Furthermore, TCE-exposed
individuals exposed at relatively low levels of TCE (<12 ppm; the median
TCE concentration among the exposed) had significant elevated KIM-1
levels as compared with the unexposed controls (P = 0.02; Figure 1).
To evaluate the influence of exposure to other chlorinated sol-
vents that were present at relatively low levels in some factories,
we excluded one factory at a time from the analyses, and found that
results were similar and conclusions unchanged (data not shown).
We found that exposure to relatively low levels of TCE (i.e. average
22 ppm) was associated with a dose-dependent increase in nephro-
toxicity markers KIM-1 and possibly Pi-GST. The association was
seen for both current TCE exposure (ppm) and cumulative TCE
exposure (ppm years). However, given the relatively short tenure of
most exposed workers (average 2 years) cumulative TCE exposure
Table I. Demographic characteristics and TCE exposure level
Subjects Unexposed (n = 45) Exposed (n = 80)
Age, mean ± SD
BMI, mean ± SD
Male n (%)
Female n (%)
Yes n (%)
No n (%)
Current alcohol use
Yes n (%)
No n (%)
Current (ppm) mean ± SD
Cumulative (ppm. years), mean ± SD
Employment in current job
Duration, Years ± SD
24.9 ± 6.0
21.5 ± 2.8
25.2 ± 6.6
21.5 ± 2.8
22.2 ± 35.9
35.8 ± 68.2
2.3 ± 2.8 2.0 ± 2.0
Table II. Renal toxicity markers by trichloroethylene exposure status
Parameter Unexposed(n = 45)aExposed(n = 80)a
P for exposed
Creatinine [mmol L−1] 11.6
VEGF [ng l−1]c
AlphaGST [µg l−1]
PiGST [µg l−1]
KIM-1 [ng l−1]
NAG [units l−1]
AMGM GSD AMGM GSD
10.3 1.7213.7 11.6 1.860.27
302.7 210.6 2.15 257.0 210.4 1.91
26.5 18.2 2.78
211.7 162.7 2.19 311.2 254.1 1.87
2.5 1.8 2.49
2.6 1.8 3.06
aAM, arithmetic mean; GM, Geometric mean; GSD, Geometric standard
bt-Test of difference in mean between ln(urinary marker) between unexposed
and exposed individuals.
cSamples of one control and three exposed subjects were not analysed for
Trichloroethylene and kidney toxicity
at University of California, Berkeley on September 1, 2012
was mostly driven by exposure intensity. An analysis with duration
among the exposed workers indeed did not show an effect with any of
the markers suggesting that the observed effect was driven predomin-
antly by current TCE exposure levels. Altogether, these data suggest
that kidney toxicity is found at occupational levels of TCE expos-
ure below the current Occupational Safety and Health Administration
permissible exposure limit of 100 ppm and below the current National
Institute of Occupational Safety and Health recommended exposure
limit of 25 ppm.
TCE exposure has been shown to be related to nephrotoxicity in
animal studies. These studies suggest that kidney damage due to TCE
can occur due to persistent cytotoxicity and regeneration (6). As in the
rats, kidney toxicity is believed to be a contributing factor to the devel-
opment of renal cancer in humans following exposure to TCE (6).
TCE-induced nephrotoxicity in humans, however, has not been dem-
onstrated conclusively partly due to methodological limitations on
exposure assessment and the use of insufficient sensitive markers (10).
In the present study, we collected extensive exposure information and
used novel sensitive nephrotoxicity markers. Our findings of kidney
toxicity at relatively low TCE levels are of importance as it indicates
that toxic metabolites are formed at these concentration levels adding
to the plausibility of the epidemiological findings linking TCE and
We did not observe an association between TCE exposure and NAG
or VEGF. NAG is mainly found in the proximal tubular brush border
cells and is shed into the urine in case of kidney damage (15,16).
VEGF is a protein involved in wound healing (16). Both biomarkers
are indicative of severe kidney damage resulting in functional loss.
The absence of an association between TCE exposure and VEGF
and NAG indicates that TCE exposure at the levels and duration
encountered in this study does not lead to severe loss of function of
Among the more sensitive nephrotoxicity markers (Pi- and
Alpha-GST and KIM-1), we found a positive association with KIM-1
and possibly Pi-GST. KIM-1 is a kidney-specific membrane protein.
In healthy cells, KIM-1 is expressed at a very low level, mostly in
the proximal tubules. KIM-1 is strongly upregulated in injured kidney
cells throughout the kidneys (17). When kidney cells are damaged, the
KIM-1 ectodomain is cleaved and shed into the urine (18). Recently,
urinary KIM-1 has been shown to outperform traditional biomarkers
of kidney injury in preclinical biomarker qualification studies (19). In
addition, in a variety of acute and chronic rodent kidney injury models
resulting from drugs and environmental toxicants (i.e. metals), KIM-1
has been shown to be a very sensitive and early diagnostic indicator
of kidney injury (19,20). KIM-1 has not been previously measured in
studies on nephrotoxicity among TCE-exposed subjects. PiGST is a
glutathione-S-transferase expressed in the distal tubules and collecting
duct cells. PiGST is shed into the urine in case of distal tubular dam-
age (21). Pi-GST has been measured in a retrospective study among
subjects with symptoms and controls by Bruning et al. (22). In con-
trast to our study, a positive association with Alpha-GST was found
but not with Pi-GST. However, given the retrospective design of this
study, it is difficult to compare the results of our cross-sectional study
with the study of Bruning et al. Green et al. (10) measured Alpha-GST
but not Pi-GST in a study among current-exposed subjects and did not
observe a difference in urinary Alpha-GST levels between exposed
and unexposed subjects. As such, the results on Alpha- and Pi-GSTs
among TCE-exposed subjects are largely inconsistent and therefore,
our borderline statistical finding of Pi-GST being related to TCE
exposure should be interpreted with caution.
We corrected our exposure-response models by including
ln(creatinine) as a continuous variable in the model. This allows for
a correction of urinary flow that is not necessarily directly propor-
tional to the urinary creatinine concentration and which can vary by
marker. We repeated our analyses by expressing the biological param-
eters without creatinine correction and per millimole creatinine and
obtained essentially the same results.
This study shows a toxic effect, as expressed by KIM-1 and possibly
Pi-GST, of inhaled TCE on the kidney at concentrations below the US
Occupational Safety and Health Administration exposure limit, which
is 100 ppm. This finding supports the biological plausibility between
TCE exposure and renal cancer.
This work was supported by intramural funds from the National
Institutes of Health, National Cancer Institute, and grants from the
Table III. Results of linear regressiona analysis of renal toxicity markers by current and cumulative trichloroethylene exposure
Ln(Current TCE exposure levels)(ppm) Ln(Cumulative TCE exposure levels)(ppm. years)
ParameterEstimate 95% CI
P-value Estimate95% CI
Ln(VEGF) [ng l−1]b
Ln(AlphaGST) [µg l−1]
Ln(PiGST) [µg l−1]
Ln(KIM-1) [ng l−1]
Ln(NAG) [units l−1]
−0.04 to 0.01
−0.04 to 0.03
−0.00 to 0.05
−0.03 to 0.08
−0.05 to 0.04
−0.05 to 0.009
−0.04 to 0.04
−0.00 to 0.06
−0.03 to 0.08
−0.06 to 0.04
a Adjusted for ln(creatinine), sex, current alcohol use, and BMI.
b Samples of one control and three exposed subjects were not analysed for VEGF.
KIM-1 Ln(ng/mmol creatinine)
Fig. 1. Box and whisker plot, demonstrating the median (line),
lower and upper interquartile range (IQR; box) and whiskers to the
highest and lowest values, excluding outliers (>1.5 times IQR; open
rounds) of KIM-1 concentration corrected for urinary creatinine
by trichloroethylene exposure category; 12 ppm was the median
trichloroethylene concentration of the exposed subjects. P-values are
from a linear model testing the pair wise difference in Ln(KIM-1)
concentration corrected for ln(creatinine), sex, current alcohol use
and BMI between the unexposed and the two exposure categories.
R.Vermeulen et al.
at University of California, Berkeley on September 1, 2012
National Institute of Environmental Health Sciences (P42ES04705 Download full-text
and P30ES01896), the Northern California Center for Occupational
and Environmental Health, and the Department of Science and
Technology of Guangdong Province, China (2007A050100004), and a
grant from the Department of Science and Technology of Guangdong
Province, P.R. China (2007A050100004 to XT). JVB was supported
by US NIH grant DK072381.
We would like to thank the participants for taking part in this study. We
thank Jackie King and the other members of the BioReliance BioRepository
(Bioreliance, Rockville, MD) for all aspects of biological sample handling,
storage and shipping, and for assisting with laboratory analysis monitoring.
JVB is the co-inventor on KIM-1 patents assigned to Partners
Healthcare, which has licensed them to a number of companies includ-
ing Genzyme, Johnson and Johnson, BiogenIdec, BioassayWorks and
R and D systems. He is a consultant to Genzyme.
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Received November 2, 2012; revised April 25, 2012; accepted May 12, 2012
Trichloroethylene and kidney toxicity
at University of California, Berkeley on September 1, 2012