Transformation of Fischer Rat Embryo Cells by the Combined Action of Murine Leukemia Virus and (-)-Trans- 9-Tetrahydrocannabinol

Price, Paul J.; Suk, William A.; Spahn, Gerard J.; Freeman, Aaron E.

doi:10.3181/00379727-140-36478

Cited by 14 publications

(15 citation statements)

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“…Hence these data show not only close association between cannabinoid exposure and various CAs but clearly indicate the existence of a threshold effect above which the teratogenic impact dramatically increases, closely mirroring in patterns of human disease the amply documented threshold effects seen in cellular, molecular, genotoxic and epigenotoxic laboratory studies [ 21 , 24 , 26 , 31 , 42 , 54 – 65 , 87 ].…”

Section: Discussionmentioning

confidence: 62%

“…For two CAs considered in detail by spatiotemporal analysis and the formal techniques of causal inference, namely small intestinal stenosis or atresia and obstructive genitourinary defects, there is clear epidemiological evidence of both close association across time and space which persists after full model adjustment, and of a causal relationship with cannabinoid including cannabidiol exposure. Moreover predictive modelling from selected spatiotemporal models demonstrates that the relationship between rising cannabidiol exposure and CA incidence is strongly sigmoidal in that both fitted curves show obvious strong positive inflections in their upper ranges which is closely and strongly reminiscent of the exponential dose-response curves observed in the laboratory in numerous genotoxic and mitochondriopathic assays [ 21 , 24 , 26 , 31 , 42 , 54 – 65 , 87 ]. P -values for this non-linearity are 2.83x10 −60 and 1.61x10 −71 respectively.…”

Section: Discussionmentioning

confidence: 85%

“…Aside from the fact of cannabis mutagenicity and genotoxicity itself one of the aspects of this subject which we find of most concern is the clear replication in many predictive geotemporospatial models of a sigmoidal relationship between cannabidiol and cannabinoid exposure and teratogenic outcomes for many congenital anomalies which is clearly highly reminiscent of the exponential dose-response relationships observed in numerous in vitro studies of cannabinoid genotoxicity and mitochondriopathy-epigenotoxicity [ 24 , 26 , 31 , 54 – 65 ]. It is the non-linear power function of dose-response between increased cannabinoid exposure and teratological outcomes which must be of particular concern to any community moving into a higher cannabinoid exposure zone.…”

Section: Introductionmentioning

confidence: 94%

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Geotemporospatial and causal inference epidemiological analysis of US survey and overview of cannabis, cannabidiol and cannabinoid genotoxicity in relation to congenital anomalies 2001–2015

Reece

Hulse

2022

BMC Pediatr

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Background Cannabinoids including cannabidiol have recognized genotoxic activities but their significance has not been studied broadly epidemiologically across the teratological spectrum. We examined these issues including contextual space-time relationships and formal causal inferential analysis in USA. Methods State congenital anomaly (CA) rate (CAR) data was taken from the annual reports of the National Birth Defects Prevention Network 2001–2005 to 2011–2015. Substance abuse rates were from the National Survey of Drug Use and Health a nationally representative longitudinal survey of the non-institutionalized US population with 74.1% response rate. Drugs examined were cigarettes, monthly and binge alcohol, monthly cannabis and analgesic and cocaine abuse. Early termination of pregnancy for abortion (ETOPFA) rates were taken from the published literature. Cannabinoid concentrations were from Drug Enforcement Agency. Ethnicity and income data were from the US Census Bureau. Inverse probability weighted (IPW) regressions and geotemporospatial regressions conducted for selected CAs. Results Data on 18,328,529 births from an aggregated population of 2,377,483,589 for mid-year analyses 2005–2013 comprehending 12,611 CARs for 62 CAs was assembled and ETOPFA-corrected (ETOPFACAR) where appropriate. E-Values for ETOPFACARs by substance trends were elevated for THC (40 CAs), cannabis (35 CAs), tobacco (11 CAs), cannabidiol (8 CAs), monthly alcohol (5 CAs) and binge alcohol (2 CAs) with minimum E-Values descending from 16.55, 1.55x107, 555.10, 7.53x1019, 9.30 and 32.98. Cardiovascular, gastrointestinal, chromosomal, limb reductions, urinary, face and body wall CAs particularly affected. Highest v. lowest substance use quintile CAR prevalence ratios 2.84 (95%C.I. 2.44, 3.31), 4.85 (4.08, 5.77) and 1.92 (1.63, 2.27) and attributable fraction in exposed 0.28 (0.27, 0.28), 0.57 (0.51, 0.62) and 0.47 (0.38, 0.55) for tobacco, cannabis and cannabidiol. Small intestinal stenosis or atresia and obstructive genitourinary defect were studied in detail in lagged IPW pseudo-randomized causal regressions and spatiotemporal models confirmed the causal role of cannabinoids. Spatiotemporal predictive modelling demonstrated strongly sigmoidal non-linear cannabidiol dose-response power-function relationships (P = 2.83x10−60 and 1.61x10−71 respectively). Conclusions Data implicate cannabinoids including cannabidiol in a diverse spectrum of heritable CAs. Sigmoidal non-linear dose-response relationships are of grave concern. These transgenerational genotoxic, epigenotoxic, chromosomal-toxic putatively causal teratogenic effects strongly indicate tight restrictions on community cannabinoid penetration.

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 94%

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Geotemporospatial and causal inference epidemiological analysis of US survey and overview of cannabis, cannabidiol and cannabinoid genotoxicity in relation to congenital anomalies 2001–2015

Reece

Hulse

2022

BMC Pediatr

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“…A rich and varied literature indicates that cannabinoid genotoxicity exhibits an exponential dose–response effect on mitochondrial inhibition, actin, tubulin, RNA, DNA and protein synthesis, chromosomal breaks, cell growth and viability, mutagenesis, epigenomic transmission of addictive behaviors and micronucleus formation which are all related to mutagenic processes [ 31 , 42 , 58–60 , 62 , 122 , 136–142 ].…”

Section: Mechanismsmentioning

confidence: 99%

Effects of cannabis on congenital limb anomalies in 14 European nations: A geospatiotemporal and causal inferential study

Reece

Hulse

2022

Environmental Epigenetics

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Background 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 (CLAR). Exponential genotoxic dose-response relationships make this investigation both intriguing and imperative. Methods Annual CLAR in 14 nations were from EUROCAT. Drug use rates were from European Monitoring Centre for Drugs and Drug Dependency. Median household income was from 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. Results Rates of CLA, hip dysplasia and the whole group of limb anomalies were higher in countries with increasing daily cannabis use (P = 1.81x10-16, 0.0005 and 2.53x10-6 respectively). In additive inverse-probability-weighted panel models the limb reduction-resin 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 mEV’s 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 3.40x1065 to 7.06 and median mEV’s 6.14x1033 to 3.41. Daily cannabis use interpolated was a more powerful metric of cannabis exposure than herb or resin THC exposure. Conclusion Data indicate that metrics of cannabis exposure are closely linked with CLAR and satisfy epidemiological criteria for causality. Along with Hawaii and 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.

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“…In lung epithelium explants, the smoke caused cell fusion, mitotic lag, and loss of contact inhibition (Leuchtenberger & Leuchtenberger 1971). THC in low concentration resembles methylcholanthrene in generating malignancy in rat embryo cells incubated with a murine leukemia virus, but is slower in action (Price et al 1972). Crude cannabis inhibits mitosis.…”

Section: Doses In Mice and Menmentioning

confidence: 97%

Cannabis and its Problems

Patón

1973

Proceedings of the Royal Society of Medicine

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Transformation of Fischer Rat Embryo Cells by the Combined Action of Murine Leukemia Virus and (-)-Trans- 9-Tetrahydrocannabinol

Cited by 14 publications

References 0 publications

Geotemporospatial and causal inference epidemiological analysis of US survey and overview of cannabis, cannabidiol and cannabinoid genotoxicity in relation to congenital anomalies 2001–2015

Geotemporospatial and causal inference epidemiological analysis of US survey and overview of cannabis, cannabidiol and cannabinoid genotoxicity in relation to congenital anomalies 2001–2015

Effects of cannabis on congenital limb anomalies in 14 European nations: A geospatiotemporal and causal inferential study

Cannabis and its Problems

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