Abnormal Development - Illegal Drugs
|Educational Use Only - Embryology is an educational resource for learning concepts in embryological development, no clinical information is provided and content should not be used for any other purpose.|
- 1 Introduction
- 2 Some Recent Findings
- 3 Illegal Drugs
- 4 Australian Data
- 5 USA Data
- 6 Cannabis
- 7 Cocaine
- 8 Heroin
- 9 Organic Solvents
- 10 Methamphetamine
- 11 Critical Periods
- 12 References
- 13 External Links
- 14 Glossary Links
This page introduces the possible effects of maternal use of illegal drugs on development. In all cases, a discussion with a medical practioner should had prior to any reproductive decision. This page has information from Australian and USA drug use surveys.There are a large number of typically used illegal drugs that may impact on development either indirectly (through maternal health) or directly (through embryonic/fetal development). In addition, there are some examples of "legal drugs" used illegally, for example in performance enhancement.
Of the 4 million women who gave birth in the United States (1992) 5% used illegal drugs while they were pregnant. This same study also showed strong link between cigarette smoking and alcohol use (legal drugs) and the use of illicit drugs in this population. Pregnant women who use drugs illicitly have also been identified as being at a greater risk for transmitting infections (e.g., HIV, HBV, HCV, syphilis, chlamydia, and gonorrhea) to their children during pregnancy or at delivery if they are infected with these pathogens.
Some Recent Findings
|More recent papers|
This table shows an automated computer PubMed search using the listed sub-heading term.
References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.
Marwa Boussada, Ridha Ben Ali, Azaa Ben Said, Khouloud Bokri, Azaiez Ben Akacha, Chedli Dziri, Michèle Véronique El May Selenium and a newly synthesized Thiocyanoacetamide reduce Doxorubicin gonadotoxicity in male rat. Biomed. Pharmacother.: 2017, 89;1005-1017 PubMed 28292009
Jelena Rakocevic, Dejan Orlic, Olivera Mitrovic-Ajtic, Miloje Tomasevic, Milan Dobric, Natasa Zlatic, Dejan Milasinovic, Goran Stankovic, Miodrag Ostojić, Milica Labudovic-Borovic Endothelial cell markers from clinician's perspective. Exp. Mol. Pathol.: 2017; PubMed 28192087
Anna Mielańczyk, Justyna Odrobińska, Sebastian Grządka, Łukasz Mielańczyk, Dorota Neugebauer Miktoarm Star Copolymers from D-(-)-salicin Core Aggregated into Dandelion-like Structures as Anticancer Drug Delivery Systems: Synthesis, Self-Assembly and Drug Release. Int J Pharm: 2016; PubMed 27771487
Pei Y Liu, Nicholas Sokolowski, Su T Guo, Faraz Siddiqi, Bernard Atmadibrata, Thomas J Telfer, Yuting Sun, Lihong Zhang, Denise Yu, Joshua Mccarroll, Bing Liu, Rui H Yang, Xiang Y Guo, Andrew E Tee, Ken Itoh, Jenny Wang, Maria Kavallaris, Michelle Haber, Murray D Norris, Belamy B Cheung, Jennifer A Byrne, David S Ziegler, Glenn M Marshall, Marcel E Dinger, Rachel Codd, Xu D Zhang, Tao Liu The BET bromodomain inhibitor exerts the most potent synergistic anticancer effects with quinone-containing compounds and anti-microtubule drugs. Oncotarget: 2016; PubMed 27764794
Panagiotis Galanos, Konstantinos Vougas, David Walter, Alexander Polyzos, Apolinar Maya-Mendoza, Emma J Haagensen, Antonis Kokkalis, Fani-Marlen Roumelioti, Sarantis Gagos, Maria Tzetis, Begoña Canovas, Ana Igea, Akshay K Ahuja, Ralph Zellweger, Sofia Havaki, Emanuel Kanavakis, Dimitris Kletsas, Igor B Roninson, Spiros D Garbis, Massimo Lopes, Angel Nebreda, Dimitris Thanos, J Julian Blow, Paul Townsend, Claus Storgaard Sørensen, Jiri Bartek, Vassilis G Gorgoulis Chronic p53-independent p21 expression causes genomic instability by deregulating replication licensing. Nat. Cell Biol.: 2016; PubMed 27323328
Below is a list of typically used illegal drugs that may impact on development either indirectly (through maternal health) or directly (through embryonic/fetal development). In some cases these are "legal drugs" used illegally, for example in performance enhancement.
- Lysergic Acid Diethylamide (LSD)
- Ecstasy, methylenedioxymethamphetamine (MDMA) -like substances
- Magic Mushrooms, psilocin and psilocybin
- Nitrous Oxide
- Organic Solvents
- Performance and Image Enhancing Drugs (PIEDs)
- Anabolic-Androgenic Steroids
- Insulin-Like Growth Factor (IGF-1)
- Human Growth Hormone (hGH)
- Creatine Monohydrate
- Human Chorionic Gonadotrophin (hCG)
- Erythropoietin (EPO)
The following statistics are based on the 1995 Australian National Drug Strategy Household survey.
- Marijuana is the most commonly used drug after tobacco and alcohol.
- 31% of persons aged 14 or more have tried it, and 13% have recently used marijuana.
- Marijuana use is no higher in South Australia or the Australian Capital Territory, where its consumption has been decriminalised.
- Analgesics is the next most frequently tried and used drug, with 12% having tried them, and 3% recently using them.
- Hallucinogens, particularly LSD, come in next at 7% ever tried, and almost 2% have used in the past 12 months. Nearly all recent users are aged under 35.
- Amphetamines have been tried by 6% of the population, and used in the past 12 months by 2%. Nearly all recent users are aged under 35.
- Cocaine has been tried by 3% of the population, and 1% have used it in the past 12 months.
- Designer drugs, particularly Ecstasy (MDMA) have been tried by nearly 3 % of the population, and used in the past 12 months by 0.8% of the population.
- Inhalants have been tried by 4% of the population, and are currently used by 0.4%
- Heroin has been tried by nearly 1% of the population, and is currently used by 0.4%.
- Illegal drugs have been injected by nearly 1.5% of the population, and currently illegal drugs are injected by .5%.
- Of the 26,355 deaths caused by drugs, 72% were due to tobacco, 25% to alcohol and 3% to illicit drugs. Alcohol is responsible for the majority of drug related deaths in persons aged 15 to 34.
- In the 1994 Urban Aboriginal and Torres Strait Islander Peoples Household survey supplement, 62% of the Aboriginal and Torres Strait Islander community drink alcohol compared to 72% of the general urban population. Those who do drink alcohol, however, consume much higher quantities of alcohol than the general population.
- 54% of urban Aboriginal and Torres Strait Islander people are current smokers, compared to 29% of the general population.
- Illicit drug use is more widespread among the Aboriginal and Torres Strait Islander urban community than in the general population. 50% have tried an illicit drug compared with 38% in the general community. 24% are current users compared with 15% in the general population with marijuana being the most popular illicit drug.
The data below is from National Institute Drug Abuse (USA) (More? NIDA Homepage)
NIDA Survey Provides First National USA Data on Drug Use During Pregnancy(September 1994)
- More than 5 percent of the 4 million women who gave birth in the United States in 1992 used illegal drugs while they were pregnant, according to the first nationally representative survey of drug use among pregnant women. The NIDA sponsored survey, which was released last fall, provides the best estimates to date of the number of women who use drugs during pregnancy, their demographic characteristics, and their patterns of drug use.
- The survey gathered self report data from a national sample of 2,613 women who delivered babies in 52 urban and rural hospitals during 1992. Based on these data, an estimated 22 1,000 women who gave birth in 1992 used illicit drugs while they were pregnant. Marijuana and cocaine were the most frequently used illicit drugs - 2.9 percent, or 119,000 women, used marijuana and another 1.1 percent, or 45,000 women, used cocaine at some time during their pregnancy.
- The survey found a high incidence of cigarette and alcohol use among pregnant women. At some point during their pregnancy, 20.4 percent, or 820,000, pregnant women smoked cigarettes and 18.8 percent, or 757,000, drank alcohol.
- The survey also uncovered a strong link between cigarette smoking and alcohol use and the use of illicit drugs in this population. Among those women who used both cigarettes and alcohol, 20.4 percent also used marijuana and 9.5 percent took cocaine. Conversely, of those women who said they had not used cigarettes or alcohol, only 0.2 percent smoked marijuana and 0. I percent used cocaine.
- Besides providing the fist national estimates of drug use during pregnancy, the survey also examined differences in the amount and types of drugs used by several racial and ethnic groups of women. Overall, 11.3 percent of African-American women, 4.4 percent of white women, and 4.5 percent of Hispanic women used illicit drugs while pregnant. While African Americans had higher rates of drug use, in ten-ns of actual numbers of users, most women who took drugs while they were pregnant were white. The survey found that an estimated 11 3,000 white women, 75,000 African-American women, and 28,000 Hispanic women used illicit drugs during pregnancy.
- The survey also described different patterns of licit and illicit drug use among white women and ethnic minorities. African-American women had the highest rates of cocaine use, mainly "crack," during pregnancy. About 4.5 percent of African-American women used cocaine compared with 0.4 percent of white women and 0.7 percent of Hispanic women who did so.
- White women had the highest rates of alcohol and cigarette use. Nearly 23 percent of white women drank alcohol and 24.4 percent smoked cigarettes. By comparison, 15.8 percent of African-American women and 8.7 percent of Hispanic women drank alcohol and 19.8 percent of African-American women and 5.8 percent of Hispanic women smoked cigarettes. "These findings point to the importance of attending to cultural issues in drug abuse prevention and treatment efforts," said Dr. Finnegan.
- Although women who used drugs during pregnancy generally decreased their rates of drug use throughout their pregnancy, they did not discontinue drug use.
- NIDA's National Pregnancy and Health Survey reveals different patterns of substance use among black, white, and Hispanic women. The survey found that an estimated 113,000 white women, 75,000 African-American women, and 28,000 Hispanic women used illicit drugs during pregnancy.
|Percent of American women who gave birth in 1992 and used drugs during pregnancy.|
Source: NIDA- Pregnancy and Drug Use Trends
|| Cannabis psychoactive ingredient is delta-9-tetrahydrocannabinol (THC).
Viviana Trezza, Vincenzo Cuomo, Louk J M J Vanderschuren Cannabis and the developing brain: insights from behavior. Eur. J. Pharmacol.: 2008, 585(2-3);441-52 PubMed 18413273
"Besides its well-known involvement in specific brain functions, such as control of movement, memory and emotions, the endocannabinoid system plays an important role in fundamental developmental processes such as cell proliferation, migration and differentiation."
Links: BBC - cannabis
|| Cocaine is an alkaloid derived from leaves of the South American shrub Erythroxylon coca.
How might cocaine interfere with brain development?"...not surprisingly, as the outcomes of different cohorts of pregnant women who use drugs are examined, diverse findings have been reported. Overall, however, children exposed to cocaine prenatally appear to have neurological and cognitive deficits. "
"Prenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. ...In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A."
"Our data show that cocaine treatment markedly inhibited the proliferation of NPCs, a phenomenon that was associated with cell cycle arrest, possibly because of increased expression of the cyclin-dependent kinase inhibitor p21. In addition, treatment of NPCs with cocaine inhibited their migratory response to CXCL12 (stromal cell-derived factor-1alpha), a finding that correlated with cocaine-induced down-regulation of CXCR4 on NPCs. Finally, these data demonstrated that NPCs exposed to cocaine underwent differentiation into cells expressing neuronal markers that was associated with an inhibition of SOX2 (SRY-related HMG-box gene 2), a transcription factor that inhibits NPC differentiation."
Cocaine exposure in utero alters synaptic plasticity in the medial prefrontal cortex of postnatal rats.
- Links: Cerebrum Development
|| The opium poppy is the original source of the synthesized opioid known as heroin (diacetylmorphine, diamorphine) and morphine. Morphine (morphine sulphate) is a drug used clinically and therapeutically as a strong analgesic (painkiller).
"Children born to heroin dependent mothers adopted at a young age and hence being raised in a good environment had normal intellectual function but a high rate of inattention and behavioral problems."
J Yanai, R A Steingart, N Snapir, G Gvaryahu, I Rozenboim, A Katz The relationship between neural alterations and behavioral deficits after prenatal exposure to heroin. Ann. N. Y. Acad. Sci.: 2000, 914;402-11 PubMed 11085339
R A Steingart, M Abu-Roumi, M E Newman, W F Silverman, T A Slotkin, J Yanai Neurobehavioral damage to cholinergic systems caused by prenatal exposure to heroin or phenobarbital: cellular mechanisms and the reversal of deficits by neural grafts. Brain Res. Dev. Brain Res.: 2000, 122(2);125-33 PubMed 10960681
- Links: NIOSH - Organic Solvents
Methamphetamine (N-methylated congener of amphetamine) is part of a family of drugs generally known as “amphetamines” (rock, ice, meth, or speed).
Amphetamines are synthetic stimulants, similar to the naturally occurring stimulant ephedrine and adrenaline, with Methamphetamine two to three times more active as a neural stimulant. Like other agents, methamphetamine toxicity increases when combined with alcohol, cocaine or opiates.
Cranial ultrasound of exposed infants have an increased incidence of intraventricular hemorrhages, echodensities, and cavitation. Intrauterine growth retardation has also been reported with these infants. Newborn neural effects have been described as reminiscent of cocaine-exposed infants showing effects on arousal and physiological stress.
As with other illegal drugs, maternal reporting mechanisms are very inaccurate. There are a variety of new detection techniques these include:
- Meconium chromatographic analysis of metabolites p-hydroxymethamphetamine (pOHMAMP), p-hydroxyamphetamine (pOHAMP), and norephedrine (NOREPH).
- Gas chromatography-mass spectrometry analysis of human placenta samples.
- Links: Australia - Prevention Research Quarterly Sep 2008 PDF | Developmental Neurotoxicity Induced by Therapeutic and Ilicit Drugs1994
The table below identifies approximate windows of time, "critical periods", that following exposure to many teratogens can lead to developmental abnormalities (anomalies, congenital). In general, the effects for each system are more severe (major anomalies) in the embryonic period during organogenesis in the first trimester. Later teratogen exposure are less severe (minor anomalies) in the fetal period during continued growth and differentiation in the second and third trimester. Note that some systems continue to develop through the fetal and postnatal periods leading to a range of different developmental outcomes.
|Conceptus||Embryonic development (weeks)||Fetal period (weeks)|
|Loss||Major abnormalities||Functional and Minor abnormalities|
- Centers for Disease Control and Prevention (CDC) Integrated prevention services for HIV infection, viral hepatitis, sexually transmitted diseases, and tuberculosis for persons who use drugs illicitly: summary guidance from CDC and the U.S. Department of Health and Human Services. MMWR Recomm Rep: 2012, 61(RR-5);1-40 PubMed 23135062
- Anna L David, Andrew Holloway, Louise Thomasson, Argyro Syngelaki, Kypros Nicolaides, Roshni R Patel, Brian Sommerlad, Amie Wilson, William Martin, Lyn S Chitty A Case-Control Study of Maternal Periconceptual and Pregnancy Recreational Drug Use and Fetal Malformation Using Hair Analysis. PLoS ONE: 2014, 9(10);e111038 PubMed 25360669 | PLoS One.
- Michael K Lindsay, Erin Burnett The use of narcotics and street drugs during pregnancy. Clin Obstet Gynecol: 2013, 56(1);133-41 PubMed 23314719
- Xavier Joya, Mario Gomez-Culebras, Alicia Callejón, Bibiana Friguls, Carme Puig, Sandra Ortigosa, Luca Morini, Oscar Garcia-Algar, Oriol Vall Cocaine use during pregnancy assessed by hair analysis in a Canary Islands cohort. BMC Pregnancy Childbirth: 2012, 12;2 PubMed 22230295
- Chris Derauf, Minal Kekatpure, Nurunisa Neyzi, Barry Lester, Barry Kosofsky Neuroimaging of children following prenatal drug exposure. Semin. Cell Dev. Biol.: 2009, 20(4);441-54 PubMed 19560049
- Rina D Eiden, Yvette Veira, Douglas A Granger Prenatal cocaine exposure and infant cortisol reactivity. Child Dev: 2009, 80(2);528-43 PubMed 19467009
- Steven E Hyman How might cocaine interfere with brain development? PLoS Med.: 2008, 5(6);e130 PubMed 18547140
- Chun-Ting Lee, Jia Chen, Teruo Hayashi, Shang-Yi Tsai, Joseph F Sanchez, Stacie L Errico, Rose Amable, Tsung-Ping Su, Ross H Lowe, Marilyn A Huestis, James Shen, Kevin G Becker, Herbert M Geller, William J Freed A mechanism for the inhibition of neural progenitor cell proliferation by cocaine. PLoS Med.: 2008, 5(6);e117 PubMed 18593214
- Shuxian Hu, Maxim C-J Cheeran, Wen S Sheng, Hsiao T Ni, James R Lokensgard, Phillip K Peterson Cocaine alters proliferation, migration, and differentiation of human fetal brain-derived neural precursor cells. J. Pharmacol. Exp. Ther.: 2006, 318(3);1280-6 PubMed 16766721
- Hui Lu, Byungkook Lim, Mu-ming Poo Cocaine exposure in utero alters synaptic plasticity in the medial prefrontal cortex of postnatal rats. J. Neurosci.: 2009, 29(40);12664-74 PubMed 19812341
- A Ornoy The impact of intrauterine exposure versus postnatal environment in neurodevelopmental toxicity: long-term neurobehavioral studies in children at risk for developmental disorders. Toxicol. Lett.: 2003, 140-141;171-81 PubMed 12676464
- S D Dixon, R Bejar Echoencephalographic findings in neonates associated with maternal cocaine and methamphetamine use: incidence and clinical correlates. J. Pediatr.: 1989, 115(5 Pt 1);770-8 PubMed 2681639
- Lynne M Smith, Linda L LaGasse, Chris Derauf, Penny Grant, Rizwan Shah, Amelia Arria, Marilyn Huestis, William Haning, Arthur Strauss, Sheri Della Grotta, Jing Liu, Barry M Lester The infant development, environment, and lifestyle study: effects of prenatal methamphetamine exposure, polydrug exposure, and poverty on intrauterine growth. Pediatrics: 2006, 118(3);1149-56 PubMed 16951010
- Lynne M Smith, Linda L Lagasse, Chris Derauf, Penny Grant, Rizwan Shah, Amelia Arria, Marilyn Huestis, William Haning, Arthur Strauss, Sheri Della Grotta, Melissa Fallone, Jing Liu, Barry M Lester Prenatal methamphetamine use and neonatal neurobehavioral outcome. Neurotoxicol Teratol: 2006, 30(1);20-8 PubMed 18031987
- Monica S Paz, Lynne M Smith, Linda L LaGasse, Chris Derauf, Penny Grant, Rizwan Shah, Amelia Arria, Marilyn Huestis, William Haning, Arthur Strauss, Sheri Della Grotta, Jing Liu, Barry M Lester Maternal depression and neurobehavior in newborns prenatally exposed to methamphetamine. Neurotoxicol Teratol: 2008, 31(3);177-82 PubMed 19059478
- Linda L LaGasse, Trecia Wouldes, Elana Newman, Lynne M Smith, Rizwan Z Shah, Chris Derauf, Marilyn A Huestis, Amelia M Arria, Sheri Della Grotta, Tara Wilcox, Barry M Lester Prenatal methamphetamine exposure and neonatal neurobehavioral outcome in the USA and New Zealand. Neurotoxicol Teratol: 2009, 33(1);166-75 PubMed 20615464
- Pedro Melo, Vicente Zanón Moreno, Sheila Pons Vázquez, Maria Dolores Pinazo-Durán, Maria Amélia Tavares Myelination changes in the rat optic nerve after prenatal exposure to methamphetamine. Brain Res.: 2006, 1106(1);21-9 PubMed 16842764
- Sarah J White, Elizabeth M Laurenzana, William Brooks Gentry, Howard P Hendrickson, David Keith Williams, Keith W Ward, Samuel Michael Owens Vulnerability to (+)-methamphetamine effects and the relationship to drug disposition in pregnant rats during chronic infusion. Toxicol. Sci.: 2009, 111(1);27-36 PubMed 19520673
- B Schutová, L Hrubá, M Pometlová, R Rokyta, R Slamberová Responsiveness to methamphetamine in adulthood is altered by prenatal exposure in rats. Physiol. Behav.: 2010, 99(3);381-7 PubMed 20006633
- Teresa R Gray, Tamsin Kelly, Linda L LaGasse, Lynne M Smith, Chris Derauf, Penny Grant, Rizwan Shah, Amelia Arria, William Haning, Sheri Della Grotta, Arthur Strauss, Barry M Lester, Marilyn A Huestis New meconium biomarkers of prenatal methamphetamine exposure increase identification of affected neonates. Clin. Chem.: 2010, 56(5);856-60 PubMed 20185623
- Xavier Joya, Mitona Pujadas, María Falcón, Ester Civit, Oscar Garcia-Algar, Oriol Vall, Simona Pichini, Aurelio Luna, Rafael de la Torre Gas chromatography-mass spectrometry assay for the simultaneous quantification of drugs of abuse in human placenta at 12th week of gestation. Forensic Sci. Int.: 2010, 196(1-3);38-42 PubMed 20056364
- Joseph Jones, Rosemarie Rios, Mary Jones, Douglas Lewis, Charles Plate Determination of amphetamine and methamphetamine in umbilical cord using liquid chromatography-tandem mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci.: 2009, 877(29);3701-6 PubMed 19783234
Thitinart Sithisarn, Don T Granger, Henrietta S Bada Consequences of prenatal substance use. Int J Adolesc Med Health: 2012, 24(2);105-12 PubMed 22909919
Viviana Trezza, Vincenzo Cuomo, Louk J M J Vanderschuren Cannabis and the developing brain: insights from behavior. Eur. J. Pharmacol.: 2008, 585(2-3);441-52 PubMed 18413273
Krzysztof M Kuczkowski The effects of drug abuse on pregnancy. Curr. Opin. Obstet. Gynecol.: 2007, 19(6);578-85 PubMed 18007137
A Ornoy The impact of intrauterine exposure versus postnatal environment in neurodevelopmental toxicity: long-term neurobehavioral studies in children at risk for developmental disorders. Toxicol. Lett.: 2003, 140-141;171-81 PubMed 12676464
Joanne P Ludlow, Sharon F Evans, Gary Hulse Obstetric and perinatal outcomes in pregnancies associated with illicit substance abuse. Aust N Z J Obstet Gynaecol: 2004, 44(4);302-6 PubMed 15282000
D A Frank, M Augustyn, W G Knight, T Pell, B Zuckerman Growth, development, and behavior in early childhood following prenatal cocaine exposure: a systematic review. JAMA: 2001, 285(12);1613-25 PubMed 11268270
Verena Metz, Birgit Köchl, Gabriele Fischer Should pregnant women with substance use disorders be managed differently? Neuropsychiatry (London): 2012, 2(1);29-41 PubMed 23243466
Scott A Shainker, Kelley Saia, Aviva Lee-Parritz Opioid addiction in pregnancy. Obstet Gynecol Surv: 2012, 67(12);817-25 PubMed 23233054
Alice Ordean, Meldon Kahan Comprehensive treatment program for pregnant substance users in a family medicine clinic. Can Fam Physician: 2011, 57(11);e430-5 PubMed 22084472
Chun-Ting Lee, Jia Chen, Teruo Hayashi, Shang-Yi Tsai, Joseph F Sanchez, Stacie L Errico, Rose Amable, Tsung-Ping Su, Ross H Lowe, Marilyn A Huestis, James Shen, Kevin G Becker, Herbert M Geller, William J Freed A mechanism for the inhibition of neural progenitor cell proliferation by cocaine. PLoS Med.: 2008, 5(6);e117 PubMed 18593214
Shelly Cambell Prenatal cocaine exposure and neonatal/infant outcomes. Neonatal Netw: 2003, 22(1);19-21 PubMed 12597088
Health Services/Technology Assessment Text (HSTAT) Bethesda (MD): National Library of Medicine (US), (2003)
Search Sep 2008 "illegal drugs and human development" 14 reference articles of which 4 were reviews.
Search PubMed: term = illegal drugs and human development | cocaine and human development | cocaine and brain development | heroin and human development | cannabis and human development | volatile organic solvent inhalation | organic solvents and development
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