This study examined the relationship between arsenic exposure, tobacco use, and lung cancer risk in a cohort of 3,278 miners in China with at least 10 years of arsenic exposure and 27 years of follow up. The results showed that lung cancer risk increased linearly with cumulative arsenic exposure and was greater at higher exposure concentrations over shorter durations compared to lower concentrations over longer durations. Joint analysis found a sub-multiplicative interaction between arsenic exposure and tobacco use, suggesting the factors influence lung cancer through different pathways. Limitations included the study only included miners with substantial arsenic exposure.

1. Arsenic, tobacco use, and lung cancer: An
occupational cohort with 27 follow-up years
Zheng Su, Meng-Na Wei, Xin-Hua Jia, Ya-Guang Fan, Fang-Hui
Zhao, Qing-Hua Zhou, Philip R Taylor, You-Lin Qiao
Environmental Research Journal (IF:6.5,Q1)
Caesar Kridha Bagus Prahartiko
D508111004

2. Outline
• Introduction
• Methods
• Results
• Discussion
• Limitations
• Conclusions
• Comments

3. Introduction

4. Introduction
• Humans exposure to arsenic can cause a range of irreversible adverse health effects
such as cancer, respiratory damage, cardiovascular diseases, and skin lesions
(World Health Organization, 2018).
• Anorganic arsenic, including ingested and inhaled arsenic, is identified as a cause
of lung cancer in humans, and evidence comes mainly from populations exposed to
high levels of arsenic in drinking water or workplace (IARC, 1987; IARC,
2004; Merian, 1981; USEPA, 2001).
• Tobacco use is the most important cause of lung cancer. It is of public and
biological importance to study whether there is an interaction between arsenic and
tobacco use on lung cancer.

5. Cont…
• Additive or multiplicative interaction refer to the combined effect of arsenic and
tobacco use larger (or smaller) than the sum or product of the individual effects
(Knol et al., 2011).
• Effect of cumulative exposure on lung cancer, either arsenic or tobacco
exposure, is influenced by exposure concentration. One is at low intensity for a
long period of time (i.e., 2 mg/m3 times 15 years); Another is at high intensity for a
short period of time (i.e., 10 mg/m3 times 3 years).
• Since the early 1960s, a series of epidemiologic studies in the Chinese Yunnan Tin
Corporation (YTC) miner reported that radon, arsenic, and tobacco use were the
main risk factors for lung cancer in the YTC (Lubin et al., 1990; Qiao et al.,
1989, 1997; Taylor et al., 1989).

6. Method

7. • Total of 3278 miners ≥40-
year-old who had 10 or
more years of arsenic
exposure were enrolled into
the full cohort, which were
used for the analysis of the
effect of arsenic on lung
cancer
• 1328 miners were used for
sensitivity analysis to assess
the robustness of the
interaction between arsenic
and tobacco use

8. Literatur
Review
• Select and Selection related
to the interaction of arsenic
and smoking. Keyword
“arsenic”, “smoking” or
“tobacco”, and “lung
cancer”

9. Literatur review

10. Arsenic Era and Exposure
• For arsenic exposure, a questionnaire was administered that included a
work history that included information on job title, workplace, and
start/stop dates by year for each job held at YTC.
• Exposure to arsenic containing ore dust was quantitatively estimated from
industrial hygiene data obtained separately for each of the four mines over
five eras and three smelters in three periods. Calculated Measures :
< 1951 0.42.
1952-9 0.06.
1960-9 0.04.
1970-9 0.03. >
1980 0.01.

11. Tobaco Use
• Information on age of start/stop smoking, type of tobacco
(cigarette,waterpipe, long-stem pipe), smoking status was collected at
baseline, and information on smoking status and type of tobacco was
collected for five consecutive years from 1992 to 1996 and they have
category if less than six months were considered never smokers and
smokers who ceased smoking at enrollment were former smokers.
• During this follow up, only 72 of 2188 (3.2%) of current smokers quit,
and only 17 of 753 (2.2%) of never smokers started smoking. However,
81 of 337 (24.0%) former smokers returned to smoking.
• For 46.9% (1540/3278) of all cohort members working in mines, exposure
to inhaled arsenic was usually accompanied by occupational radon
exposure.
Other Exposure

12. Outcome Information
• The primary outcome for this study was lung cancer incidence. Lung
cancer cases were identified from the local cancer registration agency,
medical record system, death cause systems of public security bureau, and
funeral parlor, and face-to-face interviews with relatives and workmates of
the participants.
• Lung cancer cases were confirmed via the following ways: (
1. Screen detected cases with chest radiograph and/or sputum cytological
examination;
2. Interval case with negative screening results identified by hospital due to
symptoms during the time from 1992 to 1999,
3. Other ways including data sources mentioned above.

13. Statistical Analysis
• Person-years for each miners were calculated from the date of arsenic exposure
cessation (as described above) until the date of lung cancer diagnosis, date of death,
or the administrative conclusion of the follow-up on December 31, 2018.
• In this cohort, some miners were exposed to high radon exposure at the same time
of arsenic exposure, and the mean of radon total exposure was 356.66 working level
month (WLM), slightly lower than 477.26 WLM in the radon occupational cohort.
Based on our previous findings, we applied a sub-multiplicative model to adjust for
radon exposure to clarify the arsenic-related lung cancer risks. (Lubin et al.,
1990; Qiao et al., 1989; Xuan et al., 1993).
• the mathematical formula as follows:
• formula of arsenic exposure and tobacco use was:
• All models were fitted using the Tensorflow programs by gradient descent in
Python, version 3.4.

14. Result

15. Table 1

16. Cont
This review showed that almost all studies supported the
synergism between arsenic and smoking on lung cancer

17. Cohort Information
• The full cohort of 3278 miners consisted of
2857 males and 421 females who
accumulated 73,866 person-years of
observation during which time 414 lung
cancers were identified.

19. • The ERR/mg/m3-year was 0.0033 (95% CI: 0.0014–0.0045) in
arsenic concentration <3 mg/m3 and 0.0056 (95% CI: 0.0035–
0.0073) in arsenic concentration ≥3 mg/m3

20. • variations were not statistically significant, the cumulative arsenic exposure effect
(β) and the intensity effect (φ) decreased with TSLE (change in deviance = 0.621
and p = 0.683 comparing models A0 and A1), AA (change in deviance = 0.451
and P = 0.737, models A0 vs A2), and AFE (change in deviance = 0.501 and P =
0.718, models A0 vs A3)

21. Table 4
• These joint analysis of tobacco use
and arsenic exposure showed that
the most likely model was sub-
multiplicative
• The results of the sensitivity
analysis indicated that the sub-
multiplicative interaction was
robust

22. Discussion

23. • The relationship between inhaled arsenic and lung cancer and effect modification of time factors; It
was the first time that quantitatively evaluated the joint effect between inhaled arsenic and
tobacco use on lung cancer.
• Lung cancer risks increased linearly with cumulative arsenic exposure at fixed arsenic
concentration, and for fixed cumulative arsenic exposure, risks were greater at higher
concentration for shorter duration compared with lower concentration for longer duration,
which was consistent with the Montana cohort (Lubin et al., 2008).
• The detoxified mechanisms of arsenic in human body can become limited at higher concentrations.
Inclusion criterion for this this research at least 10 years occupational arsenic exposure and lead
to higher exposure level in control group, which means our risk estimates of the arsenic effect
on lung cancer were likely underestimated.
• Arsenic-related lung cancer risks declined with time factors, but variations were not statistically
significant. (arsenic exposure had very long latency, because the risks of lung, bladder, and kidney
cancers still increased at least 40 years after exposure reduction (Smith et al., 2017))

24. Cont..
• The reported that compared with adult (≥18 yrs), the estimates were non-significantly increased
in childhood exposed to arsenic (<13 yrs). Although compelling evidence supported that young
adults after exposure to arsenic in early childhood conferred increased lung cancer risks, there
were no studies directly comparing arsenicrelated lung cancer risks in childhood and adulthood.
• Humans were extremely susceptible to early-life arsenic exposure. More importantly, arsenic
carcinogenicity has been linked to epigenetic alterations such as DNA methylation and
detoxification and excretion. In early childhood periods, rapid organogenesis and cell proliferation
allow for mutagenic, epigenetic, or other permanent carcinogenic alterations, and metabolism,
detoxification, and excretion pathways were undeveloped (Miller et al., 2002). (the morphological
and physiological features in childhood might make them more prone to arsenic exposure than
adulthood.)
• The sub-multiplicative effect shown in epidemiologic studies suggested that these two agents not
only had their own carcinogenic pathways but were involved in different stages of a multistage
process.

25. Limitation

26. Limitation
• A limitation related to this study is that the
inclusion criteria were limited to miners with a
10+ year history of arsenic. Researchers also did
not have non-exposed miner respondents.

27. Conclusions

28. Conclusions
• This study enlightened us that for fixed cumulative arsenic
exposure, higher concentration over shorter duration might be
more deleterious than lower concentration over longer
duration.
• Substantial reductions in the lung cancer burden of smokers
exposed to arsenic could be achieved by reductions in either
exposure

29. Comments

30. Comments
• This study is limited to the category of miners. My
suggestion could be expanded to not only miners,
because arsenic can also expose anyone.
• I also suggest conducting further research with a
comparative method of arsenic exposure with the
incidence of lung cancer.

31. Thank You