TY - JOUR
T1 - State Trends of Cannabis Liberalization as a Causal Driver of Increasing Testicular Cancer Rates across the USA
AU - Reece, Albert Stuart
AU - Hulse, Gary Kenneth
PY - 2022/10
Y1 - 2022/10
N2 - Background. The cause of the worldwide doubling-tripling of testicular cancer rates (TCRs) in recent decades is unknown. Previous cohort studies associated cannabis use with TCR including dose-response relationships but the contribution of cannabis to TCRs at the population level is unknown. This relationship was tested by analyzing annual trends across US states and formally assessed causality. Four US datasets were linked at state level: age-adjusted TCRs from Centers for Disease Control Surveillance Epidemiology and End Results database; drug use data from annual National Survey of Drug Use and Health including 74.1% response rate; ethnicity and median household income data from the US Census Bureau; and cannabinoid concentration data from Drug Enforcement Agency reports. Data was processed in R in spatiotemporal and causal inference protocols. Results. Cannabis-use quintile scatterplot-time and boxplots closely paralleled those for TCRs. The highest cannabis-use quintile had a higher TCR than others (3.44 +/- 0.05 vs. 2.91 +/- 0.2, mean +/- S.E.M., t = 10.68, p = 1.29 x 10(-22)). A dose-response relationship was seen between TCR and Delta 9-tetrahydrocannabinol (THC), cannabinol, cannabigerol, and cannabichromene (6.75 x 10(-9) < p < 1.83 x 10(-142)). In a multivariate inverse probability-weighted interactive regression including race and ethnic cannabis exposure (ECE), ECE was significantly related to TCR (beta-estimate = 0.89 (95%C.I. 0.36, 2.67), p < 2.2 x 10(-16)). In an additive geospatiotemporal model controlling for other drugs, cannabis alone was significant (beta-estimate = 0.19 (0.10, 0.28), p = 3.4 x 10(-5)). In a full geospatial model including drugs, income and ethnicity cannabinoid exposure was significant (cannabigerol: beta-estimate = 1.39 (0.024, 2.53), p = 0.0017); a pattern repeated at two spatial and two temporal lags (cannabigerol: beta-estimate = 0.71 (0.05, 1.37), p = 0.0.0350; THC: beta-estimate = 23.60 (11.92, 35.29), p = 7.5 x 10(-5)). 40/41 e-Values > 1.25 ranged up to 1.4 x 10(63) and 10 > 1000 fitting causal relationship criteria. Cannabis liberalization was associated with higher TCRs (ChiSqu. = 312.2, p = 2.64 x 10(-11)). Rates of TC in cannabis-legal states were elevated (3.36 +/- 0.09 vs. 3.01 +/- 0.03, t = 4.69, p = 4.86 x 10(-5)). Conclusions. Cannabis use is closely and causally associated with TCRs across both time and space and higher in States with liberal cannabis legislation. Strong dose-response effects were demonstrated for THC, cannabigerol, cannabinol, cannabichromene and cannabidiol. Cannabinoid genotoxicity replicates all major steps to testicular carcinogenesis including whole-genome doubling, chromosomal arm excision, generalized DNA demethylation and chromosomal translocations thereby accelerating the pathway to testicular carcinogenesis by several decades.
AB - Background. The cause of the worldwide doubling-tripling of testicular cancer rates (TCRs) in recent decades is unknown. Previous cohort studies associated cannabis use with TCR including dose-response relationships but the contribution of cannabis to TCRs at the population level is unknown. This relationship was tested by analyzing annual trends across US states and formally assessed causality. Four US datasets were linked at state level: age-adjusted TCRs from Centers for Disease Control Surveillance Epidemiology and End Results database; drug use data from annual National Survey of Drug Use and Health including 74.1% response rate; ethnicity and median household income data from the US Census Bureau; and cannabinoid concentration data from Drug Enforcement Agency reports. Data was processed in R in spatiotemporal and causal inference protocols. Results. Cannabis-use quintile scatterplot-time and boxplots closely paralleled those for TCRs. The highest cannabis-use quintile had a higher TCR than others (3.44 +/- 0.05 vs. 2.91 +/- 0.2, mean +/- S.E.M., t = 10.68, p = 1.29 x 10(-22)). A dose-response relationship was seen between TCR and Delta 9-tetrahydrocannabinol (THC), cannabinol, cannabigerol, and cannabichromene (6.75 x 10(-9) < p < 1.83 x 10(-142)). In a multivariate inverse probability-weighted interactive regression including race and ethnic cannabis exposure (ECE), ECE was significantly related to TCR (beta-estimate = 0.89 (95%C.I. 0.36, 2.67), p < 2.2 x 10(-16)). In an additive geospatiotemporal model controlling for other drugs, cannabis alone was significant (beta-estimate = 0.19 (0.10, 0.28), p = 3.4 x 10(-5)). In a full geospatial model including drugs, income and ethnicity cannabinoid exposure was significant (cannabigerol: beta-estimate = 1.39 (0.024, 2.53), p = 0.0017); a pattern repeated at two spatial and two temporal lags (cannabigerol: beta-estimate = 0.71 (0.05, 1.37), p = 0.0.0350; THC: beta-estimate = 23.60 (11.92, 35.29), p = 7.5 x 10(-5)). 40/41 e-Values > 1.25 ranged up to 1.4 x 10(63) and 10 > 1000 fitting causal relationship criteria. Cannabis liberalization was associated with higher TCRs (ChiSqu. = 312.2, p = 2.64 x 10(-11)). Rates of TC in cannabis-legal states were elevated (3.36 +/- 0.09 vs. 3.01 +/- 0.03, t = 4.69, p = 4.86 x 10(-5)). Conclusions. Cannabis use is closely and causally associated with TCRs across both time and space and higher in States with liberal cannabis legislation. Strong dose-response effects were demonstrated for THC, cannabigerol, cannabinol, cannabichromene and cannabidiol. Cannabinoid genotoxicity replicates all major steps to testicular carcinogenesis including whole-genome doubling, chromosomal arm excision, generalized DNA demethylation and chromosomal translocations thereby accelerating the pathway to testicular carcinogenesis by several decades.
KW - testicular cancer
KW - drugs
KW - cannabis exposure
KW - gene-environment interaction
KW - pathways and mechanisms
KW - PANEL-DATA MODELS
KW - MARIJUANA USE
KW - RISK-FACTORS
KW - DRUG-USE
KW - DELTA-9-TETRAHYDROCANNABINOL
KW - ASSOCIATION
KW - EXPOSURE
KW - MITOCHONDRIA
KW - EPIGENOMICS
KW - ADDICTION
UR - http://www.scopus.com/inward/record.url?scp=85140033265&partnerID=8YFLogxK
U2 - 10.3390/ijerph191912759
DO - 10.3390/ijerph191912759
M3 - Article
C2 - 36232059
SN - 1660-4601
VL - 19
JO - International Journal of Environmental Research and Public Health
JF - International Journal of Environmental Research and Public Health
IS - 19
M1 - 12759
ER -