The use of AA was banned in Taiwan in 2003. The authors, therefore, examined the variables of interest in the National Health Insurance Research Database and the Taiwan Cancer Registry Database between 2000 and 2016. Data were collected from 752,232 participants between the ages of 40 and 79. The cumulative dose of AA exposure (CDAE) was used to categorize individuals into a reference group (0-1 mg), a lower exposure group (1-150 mg), and a higher exposure group (>150 mg). The reference group represented 68.29% of the cohort, while 27.59% of individuals were exposed to low doses of AA, and 4.12% were exposed to high doses. A significantly higher proportion of women (36.92%) than men (26.52%) had been exposed to a CDAE of more than 1 mg (p < 0.001).
Between 2005 and 2016, 1,147 patients were diagnosed with UTUC (0.15%). There was a dose-dependent association between exposure to AA and UTUC risk (p < 0.01). Older patients had a higher risk of UTUC than younger patients. Participants living in arsenic-endemic areas were at a higher risk of developing UTUC than those in non-arsenic-endemic areas. Chronic kidney disease was the only comorbidity that was found to increase the risk of UTUC. Among individuals who had a CDAE of greater than 150 mg, the adjusted hazard ratio (aHR) was 1.96 (95% CI, 1.22 – 3.16) in 2005-2007, 3.02 (2.01 – 4.53) in 2008-2010, and 1.76 (1.09 – 2.83) in 2014-2016. A slope-change model revealed that the aHR started decreasing in 2011, seven years after the ban on AA. Based on this model that estimated an 11% decrease in aHR per year, aHR was predicted to reach 1.00 in 2018-2019. The authors subsequently performed a similar analysis on the middle-aged subgroup since the latency period depended on age (in addition to sex and CDAE). Among men between the ages of 40 and 59 with a CDAE between 1 and 150 mg, the aHR was 0.91 (0.41 – 2.01) in 2005-2007, 2.59 (1.55 – 4.33) in 2008-2010, and 1.06 (0.58 –1.95) in 2014-2016. The slope-change model indicated that aHR started to decrease in 2012 and reached 1.00 in 2014-2015 (a decrease of 19% per year). Among middle-aged men with a CDAE of greater than 150 mg, aHR was 1.51 (0.36 – 6.39) in 2005-2007, 2.57 (0.90 – 7.31) in 2008–2010, and 1.30 (0.48 – 2.49) in 2014-2016. The slope-change model showed that aHR started to decrease in 2009 and will reach 1.00 in 2020-2021 at a decrease of 6% per year. Among middle-aged women with a CDAE between 1 and 150 mg, aHR decreased from 3.30 (1.31 – 8.34) in 2005-2007 to 0.77 (0.36 – 1.68) in 2014-2016. aHR started to decrease in 2013 and reached 1.00 in 2015-2016 (rate of 28% per year). Among middle-aged women with a CDAE of more than 150 mg, the aHR decreased from 4.66 (1.61 – 13.46) in 2005-2007 to 2.09 (0.92 – 4.73) in 2014-2016. aHR started to decrease in 2011 and reached 1.00 in 2016, with a decrease of 22% per year.
The overall latency period for the development of UTUC was estimated at five to nine years after exposure to AA, revealing valuable insight relevant to public health. It should be noted that many other variables, such as exposure to other carcinogens and behaviors like smoking, may modulate the relationship between AA and UTUC risk during this period. One of the limitations of this study is the inability to account for sources of AA exposure beyond herbal prescriptions, which affect dosage associations.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
Reference:
- Jhuang JR, Chiu PC, Hsieh TC, Chen CH, Pu YS, Lee WC. Latency period of aristolochic acid-induced upper urinary tract urothelial carcinoma. Front Public Health. 2023;11:1072864. Published 2023 Mar 9. doi:10.3389/fpubh.2023.1072864
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