In the 1999 to 2001 Center for the Health and Assessment of Mothers and Children of Salinas , a longitudinal birth cohort study of families in a largely agricultural area, the median level of the pregnant adult women in an agricultural community was below the LOD of 0.1 ug/g creatinine . The 2007 to 2009 Study of Use of Products and Exposure Related Behavior , a study investigating behaviors of Northern California families that could influence exposure to environmental pollutants, reports median urinary 3PBA concentrations of 0.80 and 0.61 ug/g creatinine for children and adults respectively . The 3PBA levels in the MICASA population, 2.56 ug/g in children and 1.46 ug/g in mothers, were approximately ten times higher than those in the NHANES, CTEPP and CHAMACOS studies and approximately 3 times higher that those in SUPERB. A 2011 bio-monitoring study in which participants were recruited when they visited a health center in Jacksonville, FL, a city previously determined to have elevated rates of pesticide use, showed median urinary 3PBA levels of 2.5 ug/g in children aged 4–5 years , a value similar to the median urinary 3PBA levels found in our population. Finally, the Children’s Environmental Health Study, a prospective study following a multi-ethnic urban cohort of mothers and infants delivered at Mount Sinai Hospital in New York City, found median urinary 3PBA levels to be 19.3 ug/g in pregnant adult women living in the area during the 1998 to 2001 sampling . While the Children’s Environmental Health Study in New York City reported much higher levels,cannabis grow equipment it was suspected that the sumithrin sprayed to combat West Nile Virus in the area during the sampling campaign may have contributed to these findings .
With urinary 3PBA levels higher than the NHANES, CTEPP, Casa y Campo, SUPERB and CHAMACOS studies, and comparable to the Jacksonville, Fl study, it is clear that the MICASA population has high concentrations of 3PBA in their urine, which may be indicative of pyrethroid pesticide exposure. One possible explanation for these results is the increasing use of pyrethroids for residential spraying since the 2001 federally mandated phase-out of residential uses of the organophosphate pesticides chlorpyrifos and diazinon . However, since the NHANES 2007–2008 results show only a minimal increase in 3PBA levels from the 1999–2002 results, it is more likely that higher urinary 3PBA levels in the MICASA population are due to residing in an agricultural community with higher pesticide use and therefore exposure. We also note that some of the 3PBA in the urine may have resulted from direct exposure to 3PBA in the environment, as it has been measured in dust . It is also important to note that, although our results were validated by a GC/MS method, it is possible for cross-reactivity to occur with another common pyrethroid metabolite, 4-fluoro-3-phenoxybenzoic acid , in ELISA. This could potentially result in an over estimation of 3PBA concentrations in our study as compared to those using instrumental methods. However, the median 4F3PBA levels reported in the 2007–2008 NHANES were only 0.082 and 0.061 ug/g creatinine for children and adults, respectively . If cross-reactivity were to occur, these levels would still not account for the difference between NHANES and MICASA urinary 3PBA levels. There were few associations between the metabolite and pesticide use data from the questionnaire administered at the time of urine collection. Although 59% of the population reported having an insect problem in the home, within the previous year, only 43% reported using pesticides inside their homes and 35% reported using pesticides outside their homes.
When both adult household members were asked the pesticide use questions at baseline, 21% husband/wife pairs gave discordant answers to using indoor pesticides, and 27% gave discordant answers to using outdoor pesticides within the last year. These results suggest that actual pesticide use was higher than reported in our study and that both adult household members should be interviewed in the future in order to obtain a more accurate measure of pesticide use. There were limited associations with urinary metabolite levels and food products, with some associations, such as grapes, corresponding to crops to which pyrethroids are applied. Associations with food items where pyrethroids are not used, or used very minimally, may represent other dietary trends, or spurious correlations, as have been found in previous studies assessing food categories and pesticide metabolites in urine .There were several limitations to this study, mostly related to the use of self-reported data. One such limitation was that we were unable to obtain food serving size information due to the low educational level of this population. Additionally, as mentioned above, there was a lack of consistent reporting of pesticide applications between husband and wife. There were also limited and inconsistent relationships between housing disrepair indicators and the metabolite data. The Home Disrepair Score, a sum of participants self-reported housing disrepair indices, was significantly associated with the mother’s urinary metabolite data but only marginally associated with metabolite levels in the children. In contrast, the Inside Housing Conditions, an interviewer assessed measure of housing disrepair indices, was marginally associated with children’s urinary metabolite data with a p-value of 0.08 and was not associated with the mother’s urinary metabolite data.
A possible explanation for this inconsistency is that it was difficult for staff to assess home conditions for the Inside Housing Conditions while remaining sensitive to the participants in this community-based study. Additionally, all participants may not have consistently reported on their own housing conditions for the Home Disrepair Score.Also, there is often both within-day and between-day variability in the urinary concentrations of metabolites of non-persistent compounds like pyrethroids when only single spot urine samples are collected . Although inconsistent, the data does however support the idea that poor housing conditions lead to higher pesticide exposure, thus looking at both housing condition measurements can be an alternative mechanism in predicting pesticide exposure of people living in poorer housing conditions. As a urinary metabolite of multiple pyrethroids, 3PBA can reflect exposure from various sources, not only those in the home environment. Unfortunately there were few correlations between the urinary 3PBA concentrations and the questionnaire data. Limitations of this study were difficulties in obtaining accurate pesticide use information, food serving size information, and reliable measures for housing conditions. Harmful use of alcohol is the leading risk factor for premature disability and mortality globally among individuals aged 15 to 49 years . Excessive drinking, along with biological and environmental risk factors, can progress to alcohol use disorder , which is characterized by repeated alcohol use despite negative consequences . Notwithstanding the wide range of health and psychological consequences associated with AUD, a large treatment gap remains,mobile grow system with less than 8% of persons with past-year AUD receiving alcohol care and even fewer receiving evidence-based care . Multi-system strategies are needed to advance treatments and increase utilization rates among the diverse set of people with AUD. Development of novel, effective pharmacotherapies is one approach likely to help . To support people in recovery, medications must target factors sustaining drinking. Identifying mechanisms of action, such as through randomized controlled trials , human laboratory paradigms, and collection of real-world data represents a vital step in medications development . Behavioral pharmacology has established subjective response to alcohol as a reliable, multi-faceted phenotype serving as a central bio-behavioral marker of positive and negative reinforcement from alcohol . Individual variability in alcohol’s acute subjective effects, specifically greater stimulation and reward and lower sedation, predict liability for AUD, including escalation of alcohol use and AUD symptomatology . Positive mood, negative mood, and craving are acutely modulated by alcohol use, such that individuals typically experience an increase in positive mood and craving and decrease in negative mood along rising breath alcohol concentrations , serving as reinforcers of alcohol intake . Thus, researchers routinely assess whether pharmacotherapies can effectively modulate subjective response to alcohol through experimental human laboratory paradigms . Importantly, a recent meta-analysis has shown that medication effects on subjective responses to alcohol in the laboratory predict their efficacy in clinical trials for AUD . In an initial safety and efficacy trial, our laboratory used an intravenous alcohol administration paradigm to test whether the novel pharmacotherapy, ibudilast, modulated subjective response in a clinical sample of AUD . While ibudilast did not significantly alter subjective response, subjective effects of mood were dependent on participant’s degree of depression symptomatology.
Novel designs testing alcohol’s subjective effects are emerging, such as daily diary methods and ecological momentary assessment in which participants report on their drinking experiences in real-world settings . For instance, using EMA in an RCT that enrolled adolescents with problematic drinking, Miranda Jr. et al. found that naltrexone attenuated alcohol-induced increases in stimulation and enhanced alcohol-induced sedation, as compared to placebo. These naturalistic reports are consistent with findings on naltrexone’s subjective effects in human laboratory settings . Although less temporally precise than EMA, daily diary methods, which typically include data collection once daily, have lower participant burden and can enhance compliance. While assessment of medication effects on acute subjective response to alcohol via daily diary assessments is limited, past work has utilized these designs to assess daily relationships among urge, mood, and drinking . In a trial of naltrexone for heavy drinking among young adults, morning DDAs revealed that higher daily urge was associated with a greater likelihood of taking the medication, which in return, predicted a lower likelihood of same-day intoxication among the treatment group . The current study consists of a secondary analysis of a two-week experimental medication RCT of ibudilast, which demonstrated treatment related reductions in rates of heavy drinking, as reported through daily diary methods, and reduced neural alcohol cue-reactivity . This study seeks to further test ibudilast’s effects on subjective response to alcohol in the natural environment via DDA. When comparing participant report of drink quantity between these two methods , estimates of alcohol consumption are largely consistent, such that 75% of reports fell within 1 standard drink . Similarly, research from affective science suggests that DDA versus EMA do not meaningfully alter estimates of emotion variability in the real-world nor their associations with health outcomes . In sum, micro-longitudinal, naturalistic daily reporting is a valuable and highly complementary method to clinical trials, as they can increase power and ecological validity, reduce recall error, and result in more cost-effective RCTs . Despite a mounting body of work connecting the immune system with the development and maintenance of AUD and the important implications for the development of these novel therapeutics , few RCTs have tested immunotherapies in the context of AUD to date. Thus, our understanding of how these medications influence complex AUD profiles, including subjective response, is limited . Alcohol is believed to alter immune signaling and contribute to neuroinflammation indirectly through systemic inflammation and directly via events in the brain that stimulate release of inflammatory molecules, induce neural damage, and alter neural signaling . In preclinical models, an inflammatory state alters ethanol intake, preference, and behavioral responses to ethanol . In human AUD samples, peripheral proinflammatory markers are consistently elevated and correlate with alcohol use . As such, considerable interest exists for novel treatments that can restore healthy levels of inflammation and immune signaling to promote recovery from AUD . Phosphodiesterase inhibitors are a class of immune therapies tested extensively in preclinical models of AUD . PDEs are enzymes that play a central role in the regulation of intracellular levels of cyclic adenosine monophosphate , along with its downstream signal transductions . Acute alcohol exposure activates cAMP signal transduction, while chronic exposure to alcohol attenuates cAMP signaling pathways in specific brain regions . PDE4 isoforms are expressed in neuronal and glial cells in brain regions implicated in the rewarding and reinforcing effects of alcohol, such as the nucleus accumbens and amygdala . Ibudilast is a selective PDE inhibitor and macrophage migration inhibitory factor inhibitor that crosses the blood-brain barrier , attenuates astrocyte and microglial activation, and increases anti-inflammatory cytokine expression . Notably, preclinical work demonstrated that ibudilast reduced voluntary ethanol intake in three different rodent models of AUD . Thus, ibudilast represents a promising pharmacotherapy for AUD, but its mechanisms of action remain largely unknown in clinical samples. To date, our laboratory has tested ibudilast in two clinical samples with AUD.