Because they are lipophilic, both TCE and PCE readily distribute in the brain and body tissues and appear to cause mitochondrial dysfunction at high doses. This may partially explain the link to PD as dopaminergic neurons are sensitive to mitochondrial neurotoxicants such as MPTP/MPP+, paraquat, and rotenone.to 200–1000 mg/kg TCE over chronic time periods. While the specific metabolite or mechanism of TCE-induced neurodegeneration remains unclear, pre-clinical studies with high doses showed that mitochondrial complex I activity is dysregulated in the midbrain of rodents exposed to TCE. Mitochondrial function was further reduced in the rat striatum when TCE exposure occurred in conjunction with another PD risk factor, traumatic brain injury. The combined neurotoxic insults resulted in 50% reduction in complex I oxygen consumption, a more severe effect than each factor alone. This combined effect provides a key example of how TCE exposure may influence PD risk in certain populations, such as individuals who served in the military where head trauma is more common. In addition to combined environmental factors, evidence from preclinical studies suggests that genetic risk factors may also play a role in TCE-induced neurodegeneration. For example, in a 2021 study, chronic, systemic exposure to 200 mg/kg TCE elevated the kinase activity of LRRK2 in the striatum and substantia nigra of rats after 3 weeks, prior to the loss of dopaminergic neurons at 6 weeks. Inherited variants of LRRK2 are linked to both familial and sporadic PD, the most common of which is the G2019S mutation, that pathogenically elevate LRRK2 kinase activity resulting in dysregulated vesicular trafficking, endolysosomal dysfunction, and oxidative stress. However, despite cellular dysfunction caused by elevated LRRK2 kinase activity,ebb and flow individuals who inherit the LRRK2 G2019S mutation have only a roughly 50% increased risk for PD.

Incomplete penetrance of genetic risk factors suggests that possible gene-environment interactions could explain why only some individuals exposed to TCE develop PD and why those with a PD-related genetic predisposition may display variable risk of developing PD. Many other genetic causes of PD also affect mitochondrial function, and an interaction with TCE is conceivable for carriers of mutations in these genes. However, more data on gene-environment interaction between TCE, LRRK2,and other genetic risk factors associated with PD are needed.TCE was “ubiquitous” in the 1970s when annual U.S. production surpassed 600 million pounds per year, or over two pounds per person. About 10 million Americans worked with the chemical or other organic solvents daily; in the U.K. an estimated 8% of workers have. While domestic use has waned, the U.S. is still the top global exporter of TCE, and since 1990, occupational exposure to TCE has increased by 30% worldwide. Exposure is widespread, and a 1994 study in Italy found TCE at relatively high concentrations in the blood and urine of three quarters of a sample of the general population. Although the European Union and two U.S. states have banned TCE, it is still permitted for vapor degreasing and spot dry cleaning in the U.S. and for authorized industrial uses in the E.U.. Globally,TCE consumption is projected to increase by 3% annually, and China, which has the fastest growing rates of PD [1], now accounts for half the global market [34]. Workers can inhale or come in dermal contact with TCE, but millions more encounter the chemical unknowingly through outdoor air, contaminated groundwater, and indoor air pollution. In 1987, nearly 56 million pounds of TCE were released into the air in the U.S. alone [35]. TCE can also leak from storage tanks or be dumped into the ground where it contaminates up to one-third of the drinking water in the U.S. [36]. TCE has also polluted the groundwater in at least twenty different countries on five continents . TCE contaminates countless industrial, commercial, and military sites. TCE is found in half of the 1300 most toxic “Superfund” sites that are part of a federal clean-up program, including 15 in California’s Silicon Valley where TCE was used to clean electronics [37]. The U.S. military has stopped using TCE, but numerous sites have been contaminated, including the Marine Corps base Camp Lejeune in North Carolina. For 35 years, the base—which housed a million Marines, their families, and civilians—had levels of TCE and PCE in the drinking water 280 times safety standards.

Beginning in 1978, another route of exposure to TCE and other volatile chemicals was recognized: vapor intrusion . Researchers found that TCE, much like radon, could evaporate from contaminated soil and groundwater and enter homes, schools, and workplaces. Buildings often have lower air pressure than the outdoor environment and can draw toxic fumes through cracks in the foundation, utility lines, duct work, and elevators. This polluted air can travel upwards to apartments and offices located above plumes, which function as underground rivers of pollutant within the groundwater. TCE has been found in the indoor air of homes, in the butter in their refrigerators , and in the breast milk of nursing mothers. Since contaminated underground plumes can travel over a mile, individuals who live far from a contaminated site are still at risk. One plume on Long Island, New York, which was associated with an aerospace company, is over four miles long and two miles wide and has contaminated the drinking water of thousands . In Shanghai, China, a village, primary schools, and homes sit atop a TCE contaminated site where a chemical plant operated for over thirty years. In Newport Beach, California, multi-million dollar homes were built above a former aerospace facility known to be contaminated with TCE and PCE. In Monroe County, New York, where many of the authors of this report live, over a dozen dry cleaners have contaminated the ground with TCE.Below are seven cases where TCE may have contributed to an individual’s PD. The evidence linking possible exposure to TCE in these cases is circumstantial but raises worrisome questions about the link between the chemical and the disease. The first three cases depict likely environmental exposure contributing to PD. The latter four highlight potential risks from occupational exposure. In some cases, identifying information was changed to protect privacy.The future physician attended high school adjacent to a large computing firm where his father worked. The soil and groundwater at the manufacturing site were contaminated with TCE and PCE. In 1971, seven years before his freshman year, the well at the high school was found to have “slight contamination” with TCE even after a filtration system was installed. A generation later in 2000, groundwater monitoring found high concentrations of PCE at the manufacturing facility. Neither his homes nor his high school were ever checked for vapor intrusion despite their proximity to contaminated sites.

In 2010, after a nurse noticed that his handwriting was becoming smaller, the right-handed physician was diagnosed with writer’s cramp. Two years later, he developed constipation, a “twitch” in his right hand, and dystonia in his right arm. He was subsequently diagnosed with PD at age 38. He had no family history of and no genetic marker for PD. Two years earlier, his mother was diagnosed with breast cancer, and three years after his PD diagnosis, his father was diagnosed with prostate cancer.Pesticide exposure has been associated with increased risk of adult cancers,dry racks endocrine disruption, and neurological disorders such as Parkinson’s disease. Two studies using urine samples from the 1999–2000 National Health and Nutrition Examination Survey reported that up to 76% and 96% of the samples tested positive for metabolites of pyrethroids and organophosphates, both chemicals commonly found as ingredients in residential and agricultural pesticide formulations. It was reported that 102 million pounds of pesticide active ingredients were applied in homes and gardens in the United States in 2001. National and regional studies with self reports and/or environmental samples found that a majority of US households used pesticides in their homes, yards, and/or gardens during or in the year prior to data collection. This widespread residential pesticide use suggests that a significant portion of the population may be exposed to pesticides in their homes. However these studies did not report application patterns or information about longer term and lifetime use. Residential pesticide use data that includes information about application methods and patterns, total lifetime use, and other exposure related behaviors are needed for risk assessment and for developing population exposure models. In recent years several models have been developed to estimate residential exposure to pesticides. One model developed by the US Environmental Protection Agency is the Stochastic Human Exposure and Dose Simulation , which uses factors such as frequency of application, application type, and co-occurrence of application types to predict exposures for specified scenarios. However these models omit several factors that may affect exposure estimation such as patterns of lifetime pesticide usage, areas of a home being treated, location for pesticide storage in a home, protective measures used during application, ventilation during and after and cleaning after treatment. Our study provides information on many of these omitted factors. We recently reported on pesticide application methods and behaviors in households with young children. Here we instead focus on current and lifetime residential pesticide use in older adults, an age group that may also be especially vulnerable to toxins, such as the nervous system’s greater sensitivity to neurotoxins, and other age-related factors. To gain a better understanding of patterns and methods of residential pesticide use in older adults we will utilize information from three different studies, the Southern California cohort of elderly from the U.S.

EPA funded Study of Use of Products and Exposure Related Behaviors and the population control subjects interviewed for the Parkinson’s Environment and Genes and The Center for Gene-Environment Studies in Parkinson’s Disease studies. We have focused specifically on a population of older adults residing in an area of intense agricultural activity; therefore this population may also be exposed to pesticides from agricultural and occupational sources, as well as from residential pesticide use. For the purposes of this paper we use the term ‘pesticides’ for any chemical used to eliminate and/or control plant, animal, or insect pests in and around the residence. We hope that this descriptive study of residential pesticide use and exposure related behaviors will inform future studies of cumulative pesticide exposure to pesticides from multiple sources, as well as inform risk assessment and future modeling of pesticide exposure. We will describe the prevalence and frequency of current and lifetime use of residential pesticides; how pesticides were applied; and pesticide application related behaviors that may affect exposure. All three studies that contributed data are based on surveys of older adults residing in Fresno, Kern, and Tulare counties, located in California’s Central Valley, an area of intense agricultural activity . All three studies recruited participants from all three counties specifically selected as study areas because they are similar both demographically and in terms of intensity of agricultural activity. Since these studies collected slightly different information on residential pesticide use, we present data from all three studies in order to obtain a more comprehensive picture of lifetime pesticide use and behaviors related to pesticide use. The SUPERB study population consists of residents, age 55 years or older, recruited in three rounds from the three target counties in the California Central Valley. In the first round, beginning in November 2006, we recruited 55 participants by phone and 65 by mail; in round two, 47 participants were enrolled using a mailed screening questionnaire and follow-up phone calls. In the last round of recruitment, 306 door-to-door solicitations were conducted and enrolled 18 participants. In total, 159 participants were enrolled and 154 completed the baseline interview on pesticide use, 153 participants were used for our analysis. A more detailed description of the SUPERB study methods is available elsewhere [18]. Eligible population controls for the PEG study were at least 35 years of age, residents of Fresno, Kern, or Tulare counties, had lived in California for at least five years prior to the study, and did not have Parkinson’s Disease. Initially in 2001, for the PEG study our population controls age 65 or older were randomly selected from Medicare lists for the three counties and younger subjects from tax assessor parcel listings. However, the passage of the Health Insurance Portability and Accountability Act prohibited the use of Medicare data for these purposes; therefore we limited our recruitment strategy to using tax assessor parcels only, for subsequent enrollment. Residential parcels were randomly selected and names and phone numbers were obtained from Internet searches and marketing companies. Potential participants were contacted by phone or mail and screened for eligibility by trained study staff.

Majority of Medical cannabis preparations tested either did not contain the labeled contents or had a small % compared to the labeled amount.All medical cannabis preparations are not made equal and may have different cannabinoid content and composition.Therefore, the cannabinoid composition specific to the needs of the underlying pathobiology and symptoms needs to be selected for treatment.Outbreaks of coagulopathy from products marketed as cannabinoids but containing long-acting rodenticide raises life-threatening concerns.Commercially available, mislabeled and adulterated cannabis products pose major health risks.Therefore, awareness and education of individuals regarding potential harms of the adulterated and unreliable cannabis products needs to be raised and users and healthcare providers need to validate the reliability of the contents.While many of the aforementioned clinical studies suggest that cannabinoids may be effective therapeutic agents for treating pain, cannabinoid use in the U.S.remains controversial.The illicit use of cannabis remains a major concern due in part to racial biases in cannabis sanctions in the U.S., especially for SCD patients that mostly comprise individuals of African descent.As a Schedule I substance, federal law designates cannabis as a drug “with no currently accepted medical use and a high potential for abuse,” but medical cannabis is currently approved in 36 states, Guam, Puerto Rico, US Virgin Islands and District of Columbia.Given the growing legality of medical cannabis use,ebb and flow this substance warrants rigorous study to accurately determine its risks and benefits in SCD.There is a strong need for randomized, placebo-controlled studies to accurately determine the effects of specific cannabinoids on SCD.

Such studies require special attention to not only cannabis dosing and route of administration , but also to the chemical composition of cannabis plants due to existence of variable cannabinoid contents in cannabis plants.Access to cannabis for research purposes remains a major roadblock in the U.S.and many parts of the world despite increasing preclinical evidence suggesting that it may be a valuable strategy for treating otherwise difficult to manage pain, which may be the case in SCD.Research funding allocation for cannabis’s safe use in disease-specific manner is needed to prevent the cannabinoid epidemic before it is too late.Given the growing body of evidence supporting the potential benefits of cannabinoids for the treatment of pain in adults, but the lack of randomized, placebo-controlled studies evaluating their use in treating SCD pain, this area of research deems high significance in order to develop more effective therapeutic options requiring more effective management of sickle pain.Observing patterns in retail prices is fundamental for understanding the economics of any agricultural consumer product.The study of cannabis retail prices, like the study of other economic aspects of the cannabis industry, is fraught with difficulty, in part because cannabis remains a Schedule I narcotic under U.S.federal law.Consumer price indexes, tax records, commercial retail scanner data, industry association reports and other sources of data typically available for agricultural products such as wine, almonds and cut flowers are unavailable for cannabis.Cannabis retailers have limited access to banking services; most cannabis retail transactions are conducted in cash; and cannabis businesses are understandably reluctant to share their financial data.There is a need for better information about all aspects of the cannabis industry, including prices and price patterns.In this article, we aim to contribute to the scant literature on cannabis retail prices by describing the basic patterns of price ranges at retailers in California over a 21-month time span during which the industry underwent a series of significant regulatory changes.

Several times between October 2016 and July 2018, researchers at the UC Agricultural Issues Center gathered cannabis retail prices published on Weed maps, a leading online cannabis retail platform.We report average maximum and minimum prices for three common types of cannabis packages: one-eighth ounce of dried cannabis flower, 1 ounce of dried cannabis flower and 500-milligram cannabis-oil cartridges.In our first 11 months of data collection , we collected prices from retailers in seven representative counties around California.Next, in November 2017, we collected prices from all retailers in California that listed prices on Weed maps, while continuing to track prices in the representative counties.After mandatory licensing began in January 2018, we collected three more rounds of prices from all retailers that listed prices on Weed maps and that had received temporary licenses to operate legally from the Bureau of Cannabis Control, a state regulatory agency.Despite differences in coverage among our rounds of data collection, the data seem to represent a wide swath of cannabis retail prices for retailers that posted prices openly and were part of the legal medicinal or adult-use cannabis segments during a period of unusual change for the cannabis industry.Under California law, medicinal cannabis patients have been able to legally purchase a variety of cannabis products since the Compassionate Use Act of 1996.However, state regulation of the industry was minimal for the two decades following the passage of the Act.The legislative process that finally introduced regulation and taxation to the California cannabis market is summarized in Gold stein and Sumner and covered in greater depth in Sumner et al.and UC Agricultural Issues Center.Here we will review only the major regulatory changes that occurred between 2016 and 2018, when we were collecting price data.Proposition 64, a voter initiative, decriminalized adultuse cannabis in November 2016, the month following our first round of price data collection.The proposition — the Adult Use of Marijuana Act — eliminated criminal penalties for possession, by adults 21 and over, of up to 1 ounce of cannabis flower and/or six cannabis plants.

Changes to criminal penalties took effect almost immediately, but state regulatory agencies were given until January 1, 2018 to write regulations for licensing, safety and taxation for all legal cannabis.This left a period of about 13 months, from November 2016 to December 2017, during which California’s 20-year-old medicinal cannabis industry was able to continue operating largely as it had before AUMA: permitted but unregulated on the state level, partially and inconsistently regulated at the county and/or municipal levels and mostly untaxed on any level.During this 13-month period, medicinal retailers continued selling cannabis to state residents with up-to-date recommendations from physicians.However, some medicinal cannabis businesses faced unusual local challenges in 2017 as some cities and counties that were opposed to the establishment of an adult-use cannabis industry restricted or banned all cannabis operations from their jurisdictions.On January 1, 2018, all cannabis businesses that had not applied for temporary licenses from state agencies became illegal from the point of view of the state.The Bureau of Cannabis Control, the California Department of Food and Agriculture,dry racks the California Department of Public Health and other state agencies propagated regulations that implemented most parts of a regulatory structure that merged AUMA with previous medicinal cannabis legislation.As of January 1, 2018, licensed distributors were required to pay a 15% state excise tax on all medicinal and adult-use cannabis sold at retail, and licensed growers were expected to pay a cultivation tax of $9.25 per ounce for any cannabis that entered legal market channels in 2018.In some counties and cities, additional local taxes were imposed.All licensees were also required to follow costly new regulations governing security, age verification, handling, labeling, child-proof packaging, inventory storage and “seed-to-sale” tracking — but not yet mandatory testing, one of the costliest elements of the new regulations.A final regulatory point worth noting is that since the launch of adult-use sales in January 2018, the California cannabis retail environment has drawn little distinction between medicinal and adult-use cannabis, and we do not distinguish between the two in our reporting of retail prices.There are some differences between the medicinal and adult-use systems: Retailers need separate medicinal cannabis permits to sell medicinal cannabis; the minimum age for purchasing medicinal cannabis is 18 instead of 21; the maximum quantity that may be purchased is 8 ounces instead of 1 ounce; and purchases are exempt from sales tax if the customer has a medicinal recommendation and a county-issued medicinal ID card.However, the cannabis supply for adult-use and medicinal sales is interchangeable.Medicinal and adult-use cannabis are subject to the same testing, labeling and packaging standards.Cultivators and manufacturers have no reason to distinguish between the two product types.In general, the only substantial cost faced by a medicinal cannabis retailer who enters the adult-use market is an additional license fee.

Meanwhile, the potential market for medicinal retailers is severely limited because consumers of medicinal cannabis, if they wish their purchases to be exempt from sales tax, must obtain county identification cards for medicinal cannabis in addition to medical recommendations — at a combined cost of up to $100 per year.With adult-use cannabis now widely available, many consumers who participated in the medicinal market in 2017 chose not to renew their medicinal recommendations in 2018.From an economic perspective, the 2018 California cannabis market is thus more usefully viewed as a single market than as separate adult-use and medicinal markets.The leading source of publicly available data on U.S.cannabis retail prices is Weed maps, an internet platform that enables retailers in California and other states to publish and update their price lists, locations and other practical information on a standardized consumer-facing website and app.Weed maps has operated since 2008.Researchers have used it to study the California cannabis industry since well before the autumn of 2016, when AIC researchers first gathered information from the site.For instance, Freisthler and Gruenewald used Weed maps listings to study the industrial organization of cannabis retailers in California.We found no reliable estimates of the percentage of California retailers listed on Weed maps.But because retailers may add or remove listings from Weed maps for business or marketing reasons other than opening or closing, Weed maps provides incomplete and constantly changing coverage of California’s retail cannabis market.Bierut et al., another study that uses Weed maps data, finds that Weed maps includes about 60% of retailers in Colorado and 40% of retailers in Washington, but does not analyze California retailers on Weed maps.This uncertainty should be kept in mind when interpreting our data.We began gathering price data from Weed maps in October 2016.We recorded prices by product type and also collected information on retail sales locations and whether retailers were storefront or delivery-only operations.We collected only the minimum and maximum listed price for three of the most common cannabis products.Many retailers listed a price schedule with just two levels for each product type: entry-level and “top-shelf” prices.Some retailers maintained three to four price levels, but during the first year of data collection, we rarely encountered more than five levels.With or without intermediate prices, we had no access to information about quantities sold and could not construct quantity-weighted average prices.Moreover, cannabis strains and forms of packaging were often specific to individual retailers, and measures of specific brand or product characteristics were not consistently available on Weed maps.Considering that not all retailers list prices on Weed maps, and that some retailers who at some point listed prices on Weed maps might have removed their listings while continuing to conduct business, we supplemented our data set with prices from Leafly, a competing cannabis portal whose functionality and business model are similar to those of Weed maps.In particular, we turned to Leafly when Weed maps price information was not available for retailers whose prices we were already tracking — or, in later rounds of data collection, from retailers that had obtained licenses from the Bureau of Cannabis Control to operate in the regulated 2018 environment.Coverage provided by Weed maps and Leafly is partly overlapping: Some retailers list prices on both portals whereas others list prices only with one service or the other.To test for bias that might result from the inclusion of Leafly prices as part of our data set, we compared Weed maps and Leafly average minimum and average maximum prices in a sub-sample of non-overlapping retailers, controlling for package size, and we found no statistically significant differences between Weed maps and Leafly average minimum and average maximum prices.All retailers listed prices for one-eighth ounce of packaged flower.Not all retailers listed prices for 1 ounce of packaged flower or 500-milligram oil cartridges.In later rounds of data collection, the share of retailers listing prices for 1 ounce of flower was smaller and the share of retailers listing prices for 500 milligrams of oil was larger.For instance, in October 2016, 90% of the 542 retailers listed prices for 1 ounce of flower and 57% listed prices for 500 milligrams of oil.In August 2017, 91% of retailers still listed prices for 1 ounce of flower and 82% listed prices for 500 milligrams of oil.