Congenital anomaly epidemiological correlates of Δ8THC across USA 2003-16: panel regression and causal inferential study.
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SUBMITTER: Reece AS
PROVIDER: S-EPMC9245652 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:With reports from Australia, Canada, USA, Hawaii and Colorado documenting a link between cannabis and congenital anomalies (CAs), this relationship was investigated in Europe. Data on 90 CAs were accessed from Eurocat. Tobacco and alcohol consumption and median household income data were from the World Bank. Amphetamine, cocaine and last month and daily use of cannabis from the European Monitoring Centre for Drugs and Drug Addiction. Cannabis herb and resin Δ9-tetrahydrocannabinol concentrations were from published reports. Data were processed in R. Twelve thousand three hundred sixty CA rates were sourced across 16 nations of Europe. Nations with a higher or increasing rate of daily cannabis use had a 71.77% higher median CA rates than others [median ± interquartile range 2.13 (0.59, 6.30) v. 1.24 (0.15, 5.14)/10 000 live births (P = 4.74 × 10-17; minimum E-value (mEV) = 1.52]. Eighty-nine out of 90 CAs in bivariate association and 74/90 CAs in additive panel inverse probability weighted space-time regression were cannabis related. In inverse probability weighted interactive panel models lagged to zero, two, four and six years, 76, 31, 50 and 29 CAs had elevated mEVs (< 2.46 × 1039) for cannabis metrics. Cardiovascular, central nervous, gastrointestinal, genital, uronephrology, limb, face and chromosomalgenetic systems along with the multisystem VACTERL syndrome were particularly vulnerable targets. Data reveal that cannabis is related to many CAs and fulfil epidemiological criteria of causality. The triple convergence of rising cannabis use prevalence, intensity of daily use and Δ9-tetrahydrocannabinol concentration in herb and resin is powerfully implicated as a primary driver of European teratogenicity, confirming results from elsewhere.
| S-EPMC8824558 | biostudies-literature
Project description:The use of Δ8THC is increasing at present across the USA in association with widespread cannabis legalization and the common notion that it is "legal weed". As genotoxic actions have been described for many cannabinoids, we studied the cancer epidemiology of Δ8THC. Data on 34 cancer types was from the Centers for Disease Control Atlanta Georgia, substance abuse data from the Substance Abuse and Mental Health Services Administration, ethnicity and income data from the U.S. Census Bureau, and cannabinoid concentration data from the Drug Enforcement Agency, were combined and processed in R. Eight cancers (corpus uteri, liver, gastric cardia, breast and post-menopausal breast, anorectum, pancreas, and thyroid) were related to Δ8THC exposure on bivariate testing, and 18 (additionally, stomach, Hodgkins, and Non-Hodgkins lymphomas, ovary, cervix uteri, gall bladder, oropharynx, bladder, lung, esophagus, colorectal cancer, and all cancers (excluding non-melanoma skin cancer)) demonstrated positive average marginal effects on fully adjusted inverse probability weighted interactive panel regression. Many minimum E-Values (mEVs) were infinite. p-values rose from 8.04 × 10-78. Marginal effect calculations revealed that 18 Δ8THC-related cancers are predicted to lead to a further 8.58 cases/100,000 compared to 7.93 for alcoholism and -8.48 for tobacco. Results indicate that between 8 and 20/34 cancer types were associated with Δ8THC exposure, with very high effect sizes (mEVs) and marginal effects after adjustment exceeding tobacco and alcohol, fulfilling the epidemiological criteria of causality and suggesting a cannabinoid class effect. The inclusion of pediatric leukemias and testicular cancer herein demonstrates heritable malignant teratogenesis.
| S-EPMC9265369 | biostudies-literature
Project description:As prenatal and community cannabis exposures have recently been linked with congenital heart disease (CHD), it was of interest to explore these associations in Europe in a causal framework and space-time context. Congenital anomaly data from Eurocat, drug-use data from the European Monitoring Centre for Drugs and Drug Addiction, and income from the World Bank. Countries with rising daily cannabis use had in general higher congenital anomaly rates over time than those without (time: status interaction: β-Est. = 0.0267, P = 0.0059). At inverse probability-weighted panel regression, cannabis terms were positive and significant for CHD, severe CHD, atrial septal defect, ventricular septal defect, atrioventricular septal defect, patent ductus arteriosus, tetralogy of Fallot, vascular disruptions, double outlet right ventricle, transposition of the great vessels, hypoplastic right heart, and mitral valve anomalies from 1.75 × 10-19, 4.20 × 10-11, <2.2 × 10-16, <2.2 × 10-16, 1.58 × 10-12, 4.30 × 10-9, 4.36 × 10-16, 3.50 × 10-8, 5.35 × 10-12, <2.2 × 10-16, 5.65 × 10-5 and 6.06 × 10-10. At spatial regression, terms including cannabis were positive and significant for this same list of anomalies from 0.0038, 1.05 × 10-10, 0.0215, 8.94 × 10-6, 1.23 × 10-5, 2.05 × 10-5, 1.07 × 10-6, 8.77 × 10-5, 9.11 × 10-6, 0.0001, 3.10 × 10-7 and 2.17 × 10-7. 92.6% and 75.2% of 149 E-value estimates and minimum E-values were in high zone >9; 100.0% and 98.7% >1.25. Data show many congenital cardiac anomalies exhibit strong bivariate relationships with metrics of cannabis exposure. Causal inferential modelling for the twelve anomalies selected demonstrated convincing evidence of robust relationships to cannabis which survived adjustment and fulfilled epidemiological criteria for causal relationships. Space-time regression was similarly confirmatory. Epigenomic pathways constitute viable potential mechanisms. Given exponential genotoxic dose-response effects, careful and astute control of cannabinoid penetration is indicated.
| S-EPMC9364688 | biostudies-literature
Project description:Introduction. Of the many congenital anomalies (CAs) recently linked with community cannabis exposure, arguably the most concerning are neurological CAs (NCAs). We therefore conducted a detailed study of this in fourteen European nations. Methods. Congenital anomaly data were from Eurocat. Drug exposure data were from European Monitoring Centre for Drugs and Drug Addiction. Income from World bank. Results. The Netherlands, Spain, France and Bulgaria reported increasing rates of many NCAs. The NCA rate (NCAR) was higher in nations with increasing daily cannabis use when compared to those without (p = 0.0204, minimum E-value (mEV) = 1.35). At bivariate analysis, the mEVs of the following NCAs were significantly cannabis related: severe microcephaly 2.14 × 1013, craniosynostosis 5.27 × 1011, nervous system 4.87 × 1011, eye 2.73 × 107, microphthalmos 4.07 × 106, anencephalus 710.37, hydrocephalus 245.64, spina bifida 14.86 and neural tube defects 13.15. At inverse probability, weighted panel regression terms including cannabis were significantly related to the following series of anomalies: nervous system, anencephalus, severe microcephalus, microphthalmos, neural tube defect and spina bifida from p = 5.09 × 10−8, <2.2 × 10−16, <2.2 × 10−16, 4.84 × 10−11, <2.2 × 10−16 and 9.69 × 10−7. At geospatial regression, this same series of anomalies had terms including cannabis significant from p = 0.0027, 1.53 × 10−7, 3.65 × 10−6, 2.13 × 10−8, 0.0002 and 9.76 × 10−12. 88.0% of 50 E-value estimates and 72.0% of mEVs > 9. This analysis therefore demonstrates both close association of cannabis exposure with multiple NCAs across space-time and also fulfills the quantitative criteria of causal inferential analysis. Conclusions. Nine NCARs on bivariate and six NCARs on multivariable regression were cannabis related and fulfilled quantitative epidemiological criteria for causality and are consistent with other series. Particular concerns relate to exponential dose−response effects demonstrated in the laboratory and epidemiological studies. Great caution with community cannabinoid penetration is warranted. Data indicate that cannabis is a significant environmental teratogen and thus imply that cannabinoids should be regulated similarly to the manner in which all other important genotoxins are carefully controlled by communities for their self-sustaining longevity and the protection of generations yet to come.
| S-EPMC9819725 | biostudies-literature
Project description:As body wall congenital anomalies (BWCAs) have a long history of being associated with prenatal or community cannabis exposure (CCE), it was of interest to investigate these epidemiological relationships in Europe given the recent increases in cannabis use prevalence, daily intensity, and Δ9-tetrahydrocannabinol (THC) potency. Methods: This study makes use of BWCA data from Eurocat, drug exposure data from the European Monitoring Centre for Drugs and Drug Addiction, and income from the World Bank. Results: The mapping analysis showed that BWCARs increased in France, Spain, and the Netherlands. The bivariate mapping analysis showed that the BWCA rates (BWCAR) and the cannabis resin THC concentration rose simultaneously in France, the Netherlands, Bulgaria, Sweden, and Norway. The bivariate ranking of the BWCARs by median minimum E-value (mEV) was omphalocele > diaphragmatic hernia > abdominal wall defects > gastroschisis. With inverse probability weighted multivariable panel regression, the series of BWCAs, including gastroschisis, omphalocele, and diaphragmatic hernia, was positively related to various metrics of cannabis use from p = 2.45 × 10−14, 4.77 × 10−7 and <2.2 × 10−16. With geospatial regression, the same series of BWCAs was related to cannabis metrics from p = 0.0016, 5.28 × 10−6 and 4.88 × 10−9. Seventeen out of twenty-eight (60.7%) of the E-value estimates were >9 (high range), as were 14/28 (50.0%) of the mEVs. Conclusion: The data confirm the close relationship of the BWCARs with the metrics of CCE, fulfill the quantitative criteria of causal inference, and underscore the salience of the public health impacts of cannabinoid teratogenicity. Of major concern is the rising CCE impacting exponential cannabinoid genotoxic dose-response relationships. CCE should be carefully restricted to protect the food chain, the genome, and the epigenome of coming generations.
| S-EPMC9330494 | biostudies-literature
Project description:IntroductionSince high rates of congenital anomalies (CAs), including facial CAs (FCAs), causally attributed to antenatal and community cannabis use have been reported in several recent series, it was of interest to examine this subject in detail in Europe.MethodsCA data were taken from the EUROCAT database. Drug exposure data were downloaded from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Income was taken from the World Bank's online sources.ResultsOn the bivariate maps of both orofacial clefts and holoprosencephaly against resin, the Δ9-tetrahydrocannabinol concentration rates of both covariates increased together in France, Bulgaria, and the Netherlands. In the bivariate analysis, the anomalies could be ranked by the minimum E-value (mEV) as congenital glaucoma > congenital cataract > choanal atresia > cleft lip ± cleft palate > holoprosencephaly > orofacial clefts > ear, face, and neck anomalies. When nations with increasing daily use were compared to those without, the former had generally higher rates of FCAs (p = 0.0281). In the inverse probability weighted panel regression, the sequence of anomalies-orofacial clefts, anotia, congenital cataract, and holoprosencephaly-had positive and significant cannabis coefficients of p = 2.65 × 10-5, 1.04 × 10-8, 5.88 × 10-16, and 3.21 × 10-13, respectively. In the geospatial regression, the same series of FCAs had positive and significant regression terms for cannabis of p = 8.86 × 10-9, 0.0011, 3.36 × 10-8, and 0.0015, respectively. Some 25/28 (89.3%) E-value estimates and 14/28 (50%) mEVs were >9 (considered to be in the high range), and 100% of both were >1.25 (understood to be in the causal range).ConclusionRising cannabis use is associated with all the FCAs and fulfils the epidemiological criteria for causality. The data indicate particular concerns relating to brain development and exponential genotoxic dose-responses, urging caution with regard to community cannabinoid penetration.
| S-EPMC9944119 | biostudies-literature
Project description:BackgroundAs the cannabis-cancer relationship remains an important open question epidemiological investigation is warranted to calculate key metrics including Rate Ratios (RR), Attributable Fractions in the Exposed (AFE) and Population Attributable Risks (PAR) to directly compare the implicated case burden between emerging cannabinoids and the established carcinogen tobacco.MethodsSEER*Stat software from Centres for Disease Control was used to access age-standardized state census incidence of 28 cancer types (including "All (non-skin) Cancer") from National Cancer Institute in US states 2001-2017. Drug exposures taken from the National Survey of Drug Use and Health 2003-2017, response rate 74.1%. Federal seizure data provided cannabinoid exposure. US Census Bureau furnished income and ethnicity. Exposure dichotomized as highest v. lowest exposure quintiles. Data processed in R.ResultsNineteen thousand eight hundred seventy-seven age-standardized cancer rates were returned. Based on these rates and state populations this equated to 51,623,922 cancer cases over an aggregated population 2003-2017 of 124,896,418,350. Fifteen cancers displayed elevated E-Values in the highest compared to the lowest quintiles of cannabidiol exposure, namely (in order): prostate, melanoma, Kaposi sarcoma, ovarian, bladder, colorectal, stomach, Hodgkins, esophagus, Non-Hodgkins lymphoma, All cancer, brain, lung, CLL and breast. Eleven cancers were elevated in the highest THC exposure quintile: melanoma, thyroid, liver, AML, ALL, pancreas, myeloma, CML, breast, oropharynx and stomach. Twelve cancers were elevated in the highest tobacco quintile confirming extant knowledge and study methodology. For cannabidiol RR declined from 1.397 (95%C.I. 1.392, 1.402), AFE declined from 28.40% (28.14, 28.66%), PAR declined from 15.3% (15.1, 15.5%) and minimum E-Values declined from 2.13. For THC RR declined from 2.166 (95%C.I. 2.153, 2.180), AFE declined from 53.8% (53.5, 54.1%); PAR declined from 36.1% (35.9, 36.4%) and minimum E-Values declined from 3.72. For tobacco, THC and cannabidiol based on AFE this implies an excess of 93,860, 91,677 and 48,510 cases; based on PAR data imply an excess of 36,450, 55,780 and 14,819 cases.ConclusionData implicate 23/28 cancers as being linked with THC or cannabidiol exposure with epidemiologically-causal relationships comparable to those for tobacco. AFE-attributable cases for cannabinoids (91,677 and 48,510) compare with PAR-attributable cases for tobacco (36,450). Cannabinoids constitute an important multivalent community carcinogen.
| S-EPMC8969377 | biostudies-literature
Project description:Cannabinoid exposure is increasing in some European nations. Europe therefore provides an interesting test environment for the recently reported link between cannabis exposure and congenital limb anomaly (CLA) rates (CLARs). Exponential genotoxic dose-response relationships make this investigation both intriguing and imperative. Annual CLAR in 14 nations were from Epidemiological Surveillance of Congenital Anomalies. Drug use rates were from European Monitoring Centre for Drugs and Drug Dependency. Median household income was from the World Bank. E-values provide a quantitative measure of robustness of results to confounding by extraneous covariates. Inverse probability weighting is an important technique for equalizing exposures across countries and removing sources of bias. Rates of CLA, hip dysplasia and the whole group of limb anomalies were higher in countries with increasing daily cannabis use (P = 1.81 × 10-16, 0.0005 and 2.53 × 10-6, respectively). In additive inverse-probability-weighted panel models, the limb reduction-resin Δ9-tetrahydrocannabinol (THC) concentration E-value estimate was 519.93 [95% lower bound (mEV) 49.56], order Resin > Herb ≫ Tobacco > Alcohol. Elevations were noted in 86% E-value estimates and 70.2% of mEVs from 57 E-value pairs from inverse-probability-weighted panel models and from spatial models. As judged by the mEV the degree of association with metrics of cannabis exposure was hip dysplasia > polydactyly > syndactyly > limb anomalies > limb reductions with median E-value estimates from 3.40 × 1065 to 7.06 and median mEVs from 6.14 × 1033 to 3.41. Daily cannabis use interpolated was a more powerful metric of cannabis exposure than herb or resin THC exposure. Data indicate that metrics of cannabis exposure are closely linked with CLAR and satisfy epidemiological criteria for causality. Along with Hawaii and the USA, Europe now forms the third international population in which this causal link has been demonstrated. Cannabis as a predictor of limb anomalies was more potent than tobacco or alcohol. Cannabinoid access should be restricted to protect public health and the community genome/epigenome transgenerationally.
| S-EPMC9364687 | biostudies-literature
Project description:BACKGROUND:Cardiovascular anomalies are the largest group of congenital anomalies and the major cause of death in young children, with various data linking rising atrial septal defect incidence (ASDI) with prenatal cannabis exposure. Objectives / Hypotheses. Is cannabis associated with ASDI in USA? Is this relationship causal? METHODS:Geospatiotemporal cohort study, 1991-2016. Census populations of adults, babies, congenital anomalies, income and ethnicity. Drug exposure data on cigarettes, alcohol abuse, past month cannabis use, analgesia abuse and cocaine taken from National Survey of Drug Use and Health (78.9% response rate). Cannabinoid concentrations from Drug Enforcement Agency. Inverse probability weighted (ipw) regressions. Analysis conducted in R. RESULTS:ASDI rose nationally three-fold from 27.4 to 82.8 / 10,000 births 1991-2014 during a period when tobacco and alcohol abuse were falling but cannabis was rising. States including Nevada, Kentucky, Mississippi and Tennessee had steeply rising epidemics (Time: Status ?-estimate?=?10.72 (95%C.I. 8.39-13.05), P?<?2.0?×?10 -?16). ASDI was positively related to exposure to cannabis and most cannabinoids. Drug exposure data was near-complete from 2006 thus restricting spatial modelling from 2006 to 2014, N?=?282. In geospatial regression models cannabis: alcohol abuse term was significant (?-estimate?=?19.44 (9.11, 29.77), P?=?2.2?×?10 -?4); no ethnic or income factors survived model reduction. Cannabis legalization was associated with a higher ASDI (Time: Status ?-estimate?=?0.03 (0.01, 0.05), P?=?1.1?×?10 -3). Weighted panel regression interactive terms including cannabis significant (from ?-estimate?=?1418, (1080.6, 1755.4), P?=?7.3?×?10 -15). Robust generalized linear models utilizing inverse probability weighting interactive terms including cannabis appear (from ?-estimate?=?78.88, (64.38, 93.38), P?=?1.1?×?10 -8). Marginal structural models with machine-aided SuperLearning association of ASDI with high v. low cannabis exposure R.R.?=?1.32 (1.28, 1.36). Model e-values mostly >?1.5. CONCLUSIONS:ASDI is associated with cannabis use, frequency, intensity and legalization in a spatiotemporally significant manner, robust to socioeconomicodemographic adjustment and fulfilled causal criteria, consistent with multiple biological mechanisms and similar reports from Hawaii, Colorado, Canada and Australia. Not only are these results of concern in themselves, but they further imply that our list of the congenital teratology of cannabis is as yet incomplete, and highlight in particular cardiovascular toxicology of prenatal cannabinoid and drug exposure.
| S-EPMC7702707 | biostudies-literature
Project description:In observational studies, potential confounders may distort the causal relationship between an exposure and an outcome. However, under some conditions, a causal dose-response curve can be recovered using the G-computation formula. Most classical methods for estimating such curves when the exposure is continuous rely on restrictive parametric assumptions, which carry significant risk of model misspecification. Nonparametric estimation in this context is challenging because in a nonparametric model these curves cannot be estimated at regular rates. Many available nonparametric estimators are sensitive to the selection of certain tuning parameters, and performing valid inference with such estimators can be difficult. In this work, we propose a nonparametric estimator of a causal dose-response curve known to be monotone. We show that our proposed estimation procedure generalizes the classical least-squares isotonic regression estimator of a monotone regression function. Specifically, it does not involve tuning parameters, and is invariant to strictly monotone transformations of the exposure variable. We describe theoretical properties of our proposed estimator, including its irregular limit distribution and the potential for doubly-robust inference. Furthermore, we illustrate its performance via numerical studies, and use it to assess the relationship between BMI and immune response in HIV vaccine trials.
| S-EPMC8112616 | biostudies-literature