New Opportunities to Mitigate the Burden of Disease Caused by Traffic Related Air Pollution: Antioxidant-Rich Diets and Supplements

Air pollution is associated with premature mortality and a wide spectrum of diseases. Traffic-related air pollution (TRAP) is one of the most concerning sources of air pollution for human exposure and health. Until TRAP levels can be significantly reduced on a global scale, there is a need for effective shorter-term strategies to prevent the adverse health effects of TRAP. A growing number of studies suggest that increasing antioxidant intake, through diet or supplementation, may reduce this burden of disease. In this paper, we conducted a non-systematic literature review to assess the available evidence on antioxidant-rich diets and antioxidant supplements as a strategy to mitigate adverse health effects of TRAP in human subjects. We identified 11 studies that fit our inclusion criteria; 3 of which investigated antioxidant-rich diets and 8 of which investigated antioxidant supplements. Overall, we found consistent evidence that dietary intake of antioxidants from adherence to the Mediterranean diet and increased fruit and vegetable consumption is effective in mitigating adverse health effects associated with TRAP. In contrast, antioxidant supplements, including fish oil, olive oil, and vitamin C and E supplements, presented conflicting evidence. Further research is needed to determine why antioxidant supplementation has limited efficacy and whether this relates to effective dose, supplement formulation, timing of administration, or population being studied. There is also a need to better ascertain if susceptible populations, such as children, the elderly, asthmatics and occupational workers consistently exposed to TRAP, should be recommended to increase their antioxidant intake to reduce their burden of disease. Policymakers should consider increasing populations’ antioxidant intake, through antioxidant-rich diets, as a relatively cheap and easy preventive measure to lower the burden of disease associated with TRAP.


Introduction
Ambient air pollution is the greatest environmental risk factor for human health, being associated with considerable levels of mortality and morbidity worldwide [1]. Globally, air pollution has been estimated to result in 4.2 million premature deaths annually [1]. Traffic-related air pollution (TRAP) is a prominent source of ambient air pollution, and one of particular concern for human health [2,3]. It is estimated that almost 20% of the United States population lives near a high traffic volume road, the

Materials and Methods
We searched the following databases and search engines: PubMed, Web of Science, Science Direct, Google and Google Scholar. We focused on literature published in the past 15 years by limiting the studies to only include those published between 1 January 2004 to 18 July 2019 (time of search). Relevant studies were identified using the following keywords and keyword combinations: "air pollution and health effects", "health effects of air pollution", "oxidative stress", "oxidative stress and air pollution", "antioxidants and air pollution", "dietary intake and air pollution", "Mediterranean diet and air pollution", "dietary supplements and air pollution", "dietary interventions and air pollution", "antioxidant diet and air pollution", "nutrition and air pollution", "antioxidant polyunsaturated fatty acids", "oxidative stress and antioxidant diet and air pollution", "oxidative stress and antioxidant supplement and air pollution", and "oxidative stress and antioxidant and air pollution". Studies were exported to Mendeley reference manager software and any duplicates were removed. We also identified relevant reviews by expert knowledge.
It is worth noting that animal studies, which may have provided more evidence on antioxidants and underlying mechanisms, were excluded from this review. We decided to focus on research in human subjects due to time and resources limitations, but also because mechanistic evidence has been reviewed elsewhere [50,51], and is beyond our primary expertise.
We selected studies that met all the following criteria: Were published peer-reviewed journal articles offering insight to the relationship between antioxidant-rich diet or antioxidant supplement interventions and the adverse health effects of TRAP, or markers thereof.
Any design in human populations including cohort studies and clinical studies with controlled exposures.
We excluded studies that were: Animal studies Cell culture studies

Papers without an English translation
Papers where full text was not available Papers with pollutants or exposures not relevant to traffic Journal articles were first screened by title and abstract by J.B. Irrelevant articles were excluded while potentially relevant articles were retained. Potentially relevant articles were then screened again by reading their full text. Once again, irrelevant articles were excluded, and the remaining articles were retained for inclusion in this review. The reference lists of all articles were checked for additional relevant articles for inclusion. J.B. extracted data from included articles based on a predetermined template designed by H.K. and J.B. The data elements extracted and documented included: Study name and reference, study design, objective of the study, country of origin, population details, sample size, air pollutant(s) examined, nutrient or supplement intervention, analysis methods, key findings and notes/gaps. Other important and necessary information was extracted from articles' supplementary materials. Data extraction was done manually by J.B. and independently checked by two other authors (50% by K.S. and 100% by H.K.). A narrative synthesis was conducted in order to summarize and discuss the findings of the included studies.

Overview of Results
The literature search yielded 11 studies that fit the inclusion criteria (Table 1). Three were cohort studies and 8 were randomized controlled trials (RCTs). Sample sizes in the cohort studies ranged from 208 to 548,845 subjects. Various age groups were studied: 1 of the cohort studies examined adults age 50 to 71 years old, another examined asthmatic children between the ages of 6 and 14 and the third cohort study examined infants who were between 11 and 23 months. Sample sizes in the RCTs ranged from 29 to 267 subjects. One investigated asthmatic children between the ages of 7 and 11 years old, 5 RCTs examined healthy adults over the age of 18, whereas two used a more elderly population (50 to 72 years or over 60 years). Of the 11 studies that fit the inclusion criteria, 3 cohort studies examined participants' dietary patterns through a self-answered dietary assessment to score their fruit and vegetable intake or their Mediterranean diet adherence and 5 of the 11 studies examined the use of fish oil supplementation. Two of these 5 compared fish oil supplementation to olive oil supplementation. Fish oil is known to contain antioxidants and has beneficial action on several antioxidant/inflammatory pathways. Olive oil was used as a partial-control for fish oil, however, it should be noted that it contains oleic acid, which is a key component of the Mediterranean diet that possesses a degree of antioxidant and anti-inflammatory properties. Two of the 11 studies examined the use of sulforaphane through a broccoli sprout beverage. Finally, 1 study examined the use of a combined supplement of vitamin E and vitamin C. The included studies looked at the following air pollutants: PM 2.5 , PM 10 , concentrated ambient PM (CAP), NO 2 , O 3 , diesel exhaust particles (DEP) and benzene (Table 1). Of the 11 studies that fit the inclusion criteria, 4 were conducted in the United States, 4 in Mexico, 2 in China and 1 in Spain. Three studies addressed antioxidant-rich diets while 8 studies addressed antioxidant supplementation. In the following sections, we describe the evidence from the 11 included studies under key categories of antioxidant-rich diets and antioxidant supplementations.   Long-term exposure to PM 2.5 had statistically significant associations with cardiovascular disease (CVD), ischemic heart disease (IHD) and cerebrovascular disease. Long term exposure to NO 2 had statistically significant associations to cardiovascular disease and ischemic heart disease. Participants who had a higher alternative Mediterranean diet score had statistically significant lower rates of CVD and IHD mortality risk associated with long-term air pollution exposure.
The main limitations reported by the authors were the measures of diet were collected a baseline and the study could not account for changes in intake over time, personal covariates were only recorded at baseline and their changes could not be tracked over time, no information on residence location was available for participants that moved out of the region which could result in exposure misclassification, the cohort has a limited number of participants in races other than white and non-black Hispanic and therefore findings may not be generalized to the US population, Mediterranean dietary pattern may also reflect other overall healthy behaviors that were not fully adjusted for in this analysis. Other variables such as age, socioeconomic index, outdoor activities, atopic status, exposure to environmental tobacco smoke, use of anti-allergy medicine and season were not significant (p > 0.10) and did not alter the results by >1%. Interaction between air pollutant exposure and dietary intake was tested to assess any modifying effect of diet on adverse effect of air pollution on lung health. The effect of the nutritional indices was also assessed in children exposed to low and high levels of pollutants.
In asthmatic children, higher FVI scores were significantly associated with lower IL-8 levels in nasal lavage. In asthmatic children, children in the highest category of MDI had a higher FEV1 and FVC than children in the lowest category and this effect was statistically significant. In non-asthmatic healthy children, there were no statistically significant effects of diet.
The main limitations reported by the authors were the dietary intake food frequency questionnaire was provided by the child's mother, some error in reporting dietary intake is unavoidable, small sample size, and non-asthmatic children are known to have higher levels of antioxidants in the serum which might have inherently influenced their susceptibility to pollutants. Random-effect regression models adjusted for age, sex, heart rate, body mass index, hypertension. Subsequent models were also adjusted for systolic or diastolic blood pressure and day of the week. Analysis was stratified by hypertension diagnosis.
Reduction in heart rate variability with same day exposures to indoor PM 2.5 during the pre-supplementation phase. Participants given soybean oil supplements experienced marginal and non-significant protection from the effects of PM 2.5 on heart rate variability. Supplementation with 2 g/d of fish oil prevented heart rate variability effects related to PM 2.5 exposure in the study population.
The main limitations reported by the authors were the small sample size, the use of short-term heart rate variability recordings which might have hindered the possibility of performing an adequate assessment on very low frequencies, and the fact that the pre-supplementation phase was limited to 1 month (and consequently the confidence limit around the point estimate for the effect of PM 2.5 on heart rate variability during this phase was greater) Randomly assigned to either a placebo (sunflower seed oil) or fish oil supplementation (2.5 g per day) for 5 months with 4 rounds of follow up visits with an interval of 2 weeks in the last 2 months of the intervention.
Linear mixed effects models to evaluate PM 2.5 in relation to cardiovascular health outcomes adjusted for age, sex, body mass index, 3-day average temperature and 3-day average relative humidity.
The placebo group had statistically significantly higher levels of biomarkers of oxidative stress (higher levels of oxidized low-density lipoprotein (ox-LDL) and lower activities of antioxidant capacity), coagulation, endothelial dysfunction (higher levels of endothelin-1 and E-selectin, and lower levels of concentration of serum eNOS protein), neuroendocrine disturbance and blood inflammation than the fish oil group.
The main limitations reported by the authors were that PM 2.5 exposures were from fixed monitoring sites rather than personal monitors; healthy college age students may be less susceptible to the adverse effects of PM 2.5 and the benefits of supplementation. Another limitation is cannot exclude the potential confounding effects of daily dietary intakes of omega-3 fatty acids and other nutrients. Olive oil supplementation group experienced very low-density lipoprotein and triglyceride concentrations.
Olive oil did not provide protection in this study despite the fact it is an important part of the Mediterranean diet. The main limitations reported by the authors were the small number of participants whose results may not be applicable to the population as a whole. Another limitation is related to the fact that the exposure to air and CAP was not randomized.   After ozone exposure, children who received the placebo had statistically significant increases in interleukin-6 (IL-6) in nasal lavage while children receiving the supplement did not. Results were similar for interleukin-8 but were not significant. Uric acid decreased slightly in the placebo group.
IL-8 is a mediator of inflammation. Antioxidant supplements, such as vitamin C and E, could decrease the nasal inflammatory response to air pollutants. The main limitations reported by the authors were the exposure assessment being based on a monitoring network and not a personal measurement which could lead to misclassification of exposure, and the fact that the authors did not account for information of allergens indoors and outdoors.

Fruit and Vegetable Rich Diet
Fruits and vegetables are well known for being rich in nutrients and antioxidants. In a 2012 birth cohort study, Guxens et al. [52] analyzed the effects of antioxidants on infant mental development and its relationship to prenatal exposure to NO 2 and benzene. Prenatal exposure to air pollution was assessed by passive samplers distributed over the study areas and land use regression models were developed based on these measurements to predict average outdoor air pollution levels for the entire pregnancy at each residential address. Mothers used a self-reported food frequency questionnaire (focused on fruit and vegetable intake) during their first trimester and whether the infant was breastfed through the second year of life. A single maternal fasting blood specimen was drawn during pregnancy (mean ± SD, 13.4 ± 1.7 weeks of gestation) and maternal plasma vitamin D levels were determined. Mental development in infants between 11 and 23 months was assessed using the Bayley Scales of Infant Development. The Bayley Scales of Infant Development is composed of 163 items that assess age-appropriate mental development, performance abilities, memory, and early language skills. The results demonstrated an inverse association between both NO 2 and benzene exposure with mental development. The inverse association between pollutants and mental development was also found in infants who were not breastfed. Neither of these results were statistically significant. However, the study did result in a statistically significant inverse relationship between pollutants and mental development among infants with low maternal intake of fruits and vegetables. This study suggested that the antioxidants consumed from fruits and vegetables may inhibit the cognitive impairments in infants that might have resulted from maternal exposure to air pollutants, especially in mothers who have a low antioxidant intake.

Mediterranean Diet
The Mediterranean diet is rich in antioxidants because it is rich in plant-based foods, such as whole grains, fruits and vegetables, and olive oil [62]. It also includes low consumption of meat, moderate alcohol consumption (generally in the form of wine) and fish [63]. This diet is associated with improved cardiovascular health, reduced inflammation and reduced oxidative stress responses [64]. A large cohort study conducted in the United States had 548,845 adults between the ages of 50 and 71 used a self-reported dietary questionnaire to formulate an alternative Mediterranean diet (aMED) score based on their dietary patterns [46]. Participants who reported greater adherence to the Mediterranean diet (i.e., had a high aMED score) had significantly lower rates of cardiovascular disease mortality associated with long-term exposure to NO 2 and PM 2.5 , where long term exposure to air pollutants was determined as annual average concentration levels from 1994 to 2010. This supported the idea that greater adherence to the antioxidant-rich Mediterranean diet may blunt the adverse cardiovascular effects from air pollution exposure. Similarly, a dynamic panel cohort study of 208 children in Mexico City analyzed the relationship between fruit and vegetable intake (FVI) and Mediterranean diet index (MDI) with lung function and airway inflammation. Readings from the closest fixed site monitoring station were assigned to the child's residential address and used to estimate their exposure to PM 2.5 , NO 2 , and O 3 . Children were followed for 22 weeks, with their pulmonary function measured every 2 weeks, and their nasal lavage was collected and analyzed for inflammatory markers. Asthmatic children with a higher FVI scores had statistically significant lower interleukin-8 (a mediator of inflammation, IL-8) in their lavage after exposure to PM 2.5 , NO 2 , and O 3 . Children who had high FVI scores had 8% lower IL-8 than children with low FVI scores. Furthermore, asthmatic children who had higher MDI scores had significantly higher lung function after exposure to PM 2.5 , NO 2 , and O 3 [53]. Children with the highest MDI scores had a 15.3% higher forced expiratory volume in one second and 16.5% higher forced vital capacity than children with lower MDI scores, which indicates increased lung functioning in those with higher MDI scores [53]. However, no statistically significant protection from inflammation and reductions in lung function were found in the non-asthmatic children.

Fish Oil and Other Oil Supplements
Fish oil and (to a lesser extent) soy oil have anti-inflammatory effects and have been shown to reduce ROS generation and mitigate the oxidative stress response from stimuli, including air pollution [65]. In a randomized, double-blinded, controlled trial, the effects of fish oil were compared to the effects of soy oil in 50 nursing home residents (all >60 years old) who had been exposed to elevated levels of PM 2.5 from the ambient air. The participants spent 93% of their time indoors, and the mean levels of ambient PM 2.5 in the room where the study was conducted was 18.6 µg/m 3 (24 h average). This study was in Mexico City, where the major source of PM 2.5 pollution is vehicular traffic and a large proportion of vehicles use diesel fuel. The mean levels of ambient PM 2.5 outdoors during the study period was 19.6 µg/m 3 (24 h average). Participants were given either 2 g of soy oil per day (control) or 2 g of fish oil per day with a 6-month monitoring period (1-month pre-supplementation and 5 months supplementation). In the pre-supplementation phase, the group receiving fish oil supplements experienced a 54% reduction in parameters of heart rate variability (HRV); high frequency log10-transformed HRV associated with a 1 standard deviation change in PM 2.5 exposure. During the supplementation phase, this reduction was 7%. Participants who were given 2 g of fish oil supplements per day experienced a statistically significant reduction in their heart rate variability (HRV) decline after being exposed to PM 2.5 . On the other hand, participants who were given soy oil supplements experienced marginal and non-significant changes in HRV after PM 2.5 exposure [54]. Decreased HRV has been associated with increased mortality from sudden death and ventricular arrhythmia in both healthy and diseased individuals [57], thus the fish oil supplement suggest a beneficial effect whereas the soy oil did not.
In another RCT conducted by the same authors [55], 52 participants from a nursing home were given similar supplements of fish oil or soy oil for 4 months. Participants spent 93% of their time indoors where they were chronically exposed to ambient PM 2.5 with a mean daily concentration of 38.7 µg/m 3 . Both fish oil and soy oil groups increased plasma levels of superoxide dismutase (SOD) activity and increases in levels of reduced glutathione (GSH) demonstrating systemic efficacy of the antioxidant supplements (both SOD and GSH are key antioxidant mediators). Additionally, the fish oil, but not the soy oil, group showed decreases in levels of lipoperoxidation (LPO), a marker of oxidative stress. A similar randomized, double-blinded, placebo-controlled trial in China analyzed the extent to which fish oil supplements (2.5 g per day) would protect against cardiovascular damage as a result of PM 2.5 exposures. The participants were 65 healthy, college students (20 to 25 years old) who underwent a 5-month supplementation phase with 4 rounds of follow up visits with an interval of 2 weeks in the last 2 months of the intervention. In this study, the placebo group was given sunflower seed oil. There was greater levels of oxidative stress (higher levels of ox-LDL and lower activities of antioxidant capacity), inflammation and coagulation biomarkers, as well as endothelial dysfunction (higher levels of endothelin-1 and E-selectin, and lower levels of concentration of serum eNOS protein), and neuroendocrine disturbance in the placebo group compared to the fish oil supplement group [56].
Another RCT conducted in the United States found that healthy individuals (20 participants aged 50 to 72) given fish oil supplements (3 g per day) for 4 weeks prior to sequential 2 h chamber exposures to CAP and ultrafine particulate matter (mean: 278 ± 19 µg/m 3 ), were protected from autonomic, cardiac electrophysiological, and lipid changes [57]. Cardiac electrophysiological changes were measured through HRV and cardiac repolarization while lipid levels and blood cells were analyzed to indicate lipid changes. Participants who received a similar olive oil supplement were unprotected from cardiac electrophysiological and lipid changes. Fish oil supplementation attenuated CAP-induced reductions in high frequency/low frequency ratio and elevations in normalized low-frequency HRV. Furthermore, participants who consumed olive oil supplements experienced significant increases in their normalized low-frequency HRV immediately after exposure to CAP, which persisted for at least 20 h, while those given the fish oil supplements did not experience any significant alteration in HRV in response to CAP exposures [57]. Furthermore, one RCT investigated the effect of olive oil compared to fish oil in mitigating endothelial dysfunction (a marker and risk factor for cardiovascular disease) and coagulation markers in response to a two-hour controlled exposure to CAP (mean: 253 ± 16 µg/m 3 , by drawing ambient air from above the roof and passing it through a 2-stage aerosol Harvard concentrator that produces up to a 30-fold increase in particle number and mass) in 42 middle-aged volunteers. Participants who consumed 3 g of olive oil per day for 28 days experienced a statistically significant increase in flow mediated dilation and increases in fibrinolysis blood markers which indicate a protective effect to attenuate vascular effects of exposure to CAP. This effect was not seen in participants consuming 3 g of fish oil per day [58]. These results warrant further investigation because other studies found that fish oil supplements provided protection from air pollutants.

Sulforaphane
Sulforaphane is a molecule often found in cruciferous vegetables, such as broccoli, that has anti-inflammatory and antioxidant properties [66]. Due to its antioxidant nature, sulforaphane has been investigated for its ability to mitigate the adverse health effects of TRAP. Previous research conducted to investigate the effects of sulforaphane on the expression of oxidative stress genes revealed that sulforaphane had detoxification properties that could provide protection from the harm brought on by air pollutants [67].
A single blinded, placebo-controlled trial was conducted to analyze the effects of standardized broccoli sprout extract on nasal inflammatory response after exposure to DEP. DEP exposures of 300 µg in an aqueous suspension were administered from a dilution tunnel constant volume sampler. A standardized dose of 100 micromolar sulforaphane broccoli sprout extract in mango juice was given to 29 healthy adult participants for four consecutive days. Participants consuming the juice exhibited a lower inflammatory response (white blood cell counts) to the DEP compared to the control. [59]. Another randomized, placebo-controlled trial in China investigated whether daily consumption of a broccoli sprout beverage for 12 weeks could ameliorate the detrimental effects of benzene exposure. Participants who received the broccoli sprout beverage had a statistically significant higher urinary S-phenyl mercapturic acid (SPMA) and hydroxypropyl mercapturic acid (3-HPMA) excretion [60]. SPMA and 3-HPMA are markers for exposure to benzene air pollution because they are levels of mercapturic acids formed in the metabolism of benzene. These levels increase as a result of benzene exposure. Increased level of excretion of SPMA and 3-HPMA indicates that the broccoli sprout beverage enhanced detoxification of pollutants. While the broccoli sprout beverages prove to be useful in mitigating the adverse effects associated with the exposures to DEP and benzene, participants in the studies often complained of the beverage's bad taste, and some experienced nausea from the drink.

Vitamin C and Vitamin E
Vitamin C and vitamin E have been the focus of several studies due to being inexpensive antioxidants that are widely taken as supplements across the world. In a randomized, double blinded, placebo-controlled trial conducted in Mexico, asthmatic children (7 and 11 years) were given a supplement comprising of 50 mg vitamin E and 250 mg vitamin C with measurements of nasal lavages were taken 3 times during a 4 month follow up and analyzed for content of interleukin-6, IL-8, uric acid, and glutathione. Children who received the placebo had statistically significant increases in interleukin-6 (IL-6; a marker of inflammation) in nasal lavage that was associated with O 3 and PM 10 exposure, while children receiving the antioxidant supplement did not [61]. However, the study did not account for information regarding allergens, which limits the results.

Summary and Key Findings
This literature review provides evidence that antioxidant-rich diets and antioxidant supplements can protect against the adverse health effects associated with exposure to air pollution, and specifically, TRAP. The evidence is largely consistent and originates from RCTs with relatively small numbers of volunteers and a limited number of population-based cohort studies. The data suggests that increased antioxidant intake, whether it be through diet or supplementation, can blunt the adverse health effects of exposure to common traffic-related air pollutants. However, the number of studies investigating this question is rather small (11) and further research is required to replicate and confirm previous findings.
Antioxidant-rich diets, such as the Mediterranean diet and increased fruit and vegetable intake, gave the most promising evidence for protection from TRAP. On the other hand, the benefits of olive oil, a feature of the Mediterranean diet, were inconsistent between studies. These results warrant further research in order to determine the effectiveness of olive oil in mitigating adverse health effects from TRAP exposure. In contrast, fish oil supplements provided more consistently effective results in mitigating the effects of TRAP. Fish oil supplements are relatively cheap and can be accessed easily without prescription. In addition to taking fish oil supplements, people could also increase their intake through diet by consuming fish rich in oils (n-3-PUFA). Fish that are rich in n-3-PUFA include sockeye salmon, farmed trout and salmon, Copper River salmon, Coho salmon, bronzini, and toothfish [68]. The effective dose of fish oil (in diet or as supplements) requires further research. Broccoli sprout beverages containing sulforaphane also mitigated the adverse health effects of TRAP exposure, albeit only two studies that were identified. However, people may be unlikely to consume a broccoli sprout beverage regularly if they dislike the taste or experience side effects such as mild gastrointestinal upset [59]. Finally, vitamin C and vitamin E were investigated in one study and were found to reduce inflammation associated with air pollution exposure. While the evidence suggests that vitamin C and E supplements may be useful in providing protection from TRAP, the overall findings of large clinical trials of these antioxidants assessing mortality and clinically-relevant end-points have been disappointing [69]. Concerningly, a meta-analysis of 19 clinical trials using vitamin E supplements found that high doses (≥400 IU/d for at least 1 year) of vitamin E may even increase all-cause mortality [70]. Vitamin C and E should therefore not be taken in high doses and consumed with precaution until there is more research to determine their effective dose to protect from pollutants. For all anti-oxidants identified in the literature, more research is needed to determine their appropriate dosages. Once the effective dose for each of these supplements is determined, they could offer a relatively cheap and accessible method to increase antioxidant intake, thus increasing protection from TRAP. Other factors to be considered when investigating the effectiveness of antioxidant supplementation would be the time the antioxidant is consumed, duration of supplementation, the balance between diet and supplementation, the amount of antioxidants that reach the bloodstream and whether or not antioxidants reach the areas of disease or subcellular locations. Further points of interest include what formulations can be used to increase bioavailability of antioxidants, whether formulations can be used to target specific organs or diseases, whether antioxidants combat only some parts of the disease pathways and not others, if are antioxidants useful for specific patient subgroups and not others, and finally, whether combinations of antioxidants needed to fully target multiple free radicals and disease processes.
Based on the results of this review, increasing people's fruit and vegetable intake as well as encouraging adherence to the Mediterranean diet seem to be the most promising strategy. In addition to offering protection against TRAP effects, dietary interventions are associated with other co-benefits, such as reduced mortality and reduced risk of diseases overall by decreasing the inflammatory response associated with exposure and mitigating oxidant damage to cell structures [69]. Furthermore, dietary changes that increase antioxidant intake should be encouraged for all people, and especially for susceptible populations such as children, the elderly, asthmatics and those who are occupationally exposed to TRAP. Those who suffer from preexisting chronic conditions and chronic inflammation [48] and those who have damaged or weakened antioxidant defense systems may be more susceptible to oxidative stress [71]. Children are also a susceptible population because their organ systems are still developing, and therefore there is a greater cellular susceptibility to oxidative stress. Likewise, elderly persons have an increased susceptibility due to weakened immune and detoxification systems. Transportation workers, taxi drivers, construction workers, and street vendors may experience greater exposures to TRAP due to their occupational location and/or type of work. Indeed, a study revealed that taxi drivers had higher levels of oxidative stress biomarkers, increases in pro-inflammatory mediators and an increased risk for cardiovascular events, compared to non-occupationally exposed persons [72]. Genetic abnormalities can also engender greater susceptibility to more oxidative stress [73]. Polymorphisms in genes involved in oxidative stress such as NAD(P)Quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase (GSTM1 or GSTP1) have been found to alter response to pollutants. For example, genetic variations in these genes led to a greater nasal inflammation, increased airway epithelial damage, and higher levels of oxidative stress in response to O 3 exposure [73]. It is worth noting that 5 of the 11 articles included in this review investigated populations of potential susceptibility. Two RCTs enrolled elderly participants, 1 RCT enrolled asthmatic children, 1 cohort study investigated children, and 1 considered prenatal exposures of infants.

Comparison with Previous Studies
The findings of this literature review are consistent with findings of previous relevant studies. For instance, a RCT in 80 adults in Brazil investigated the effect of antioxidant supplementation (6 month of 500 mg of vitamin C and 800 mg of vitamin E) on biomarkers of oxidative stress linked to PM exposure originating from coal combustion emissions [74]. While this study is specifically not a TRAP exposure, there are similarities between the health effects of both these combustion-derived emissions and their pathways of action. Level of exposure was determined by whether people were directly exposed (those who handle the mineral coal), indirectly exposed (office workers of the electric power plant 200 m from the burning area), residents (subjects living in the city 2 kilometers from the burning area) or non-exposed subjects (controls who lived 100 km from the emissions). After taking the antioxidant supplement for 6 months, participants in all groups who were exposed to PM emissions (direct exposure, indirect exposure, and residents) had similar levels of biomarkers of oxidative stress as the control group [74].
Older studies before time frame for this literature review's search criteria also present evidence that antioxidant supplementation can mitigate the adverse health effects of air pollution. A controlled trial in the Netherlands, investigated the use of a supplement (650 mg of vitamin C, 75 mg of vitamin E and 15 mg of beta carotene) in 26 young amateur cyclists exposed to O 3 . The cyclists who took the supplement experienced no effect from the O 3 exposure on lung function (forced expiratory volume in one second, forced vital capacity, peak expiratory flow, and maximal mid expiratory flow) while the control group that received a placebo had adverse responses to O 3 [75]. A double-blinded randomized trial in 158 children with asthma in Mexico City investigated the use of daily supplementation (50 mg of vitamin E and 250 mg of vitamin C). This study revealed that daily antioxidant supplementation provided protection against exacerbation of asthma symptoms from O 3 and NO 2 exposures [76]. Both studies provide more evidence supporting the claim that vitamin E and vitamin C can mitigate pulmonary decrements after exposure to traffic-related air pollutants and secondary pollutants (e.g., O 3 which is promoted by traffic-related emissions).

Limitations
We did not intend this literature review to be an all-inclusive review of antioxidant interventions studied in relation to air pollution. Instead, we focused on human studies in the last 15 years, to provide a summation of recent findings that have relevance to TRAP and highlight key research findings and gaps from the most up-to-date evidence base. We acknowledge that the current review was non-systematic, searching specific databases and being limited to the last 15 years. Conducting a systematic review is likely to identify further evidence and potentially different conclusions. Furthermore, there is a substantial body of preclinical data from animals and cellular models that could provide useful mechanistic insight into the human observations.
Another potential limitation of this review stems from the limitations of the studies analyzed and the methodologies employed in the included papers. For example, RCTs are not representative of the combination of TRAP exposures people experience in the real-world. Instead, they are usually limited to specific pollutants being tested in each experiment through controlled exposures. On the other hand, there are many benefits of controlled exposure studies over real-world investigations due to their ability to control exposures at specific rates over specific time periods and the minimization of bias, especially selection bias and confounding. Another limitation relates to the exposure assessment in the included studies. Often, exposure assessment was based on a fixed monitoring network rather than a personal monitor, which could lead to exposure misclassification. The increased availability of more accurate lower-cost personal sensors will allow gathering of more accurate individual exposures, or at the very least offer insight into the potential uncertainty arising from use of fixed monitoring data. The literature identified considered studies conducted in different geographic areas, which provides some benefits in terms of ascertaining the generalization of the observed effects in different populations. However, it also introduces other factors that could be confounders (e.g., different air pollution mixtures in different regions, genetic background, socioeconomic variables, differences in diet, and compliance for taking supplements). Finally, in several of the antioxidant supplement studies, some aspects of participants' diets were not controlled for or only adjusted for at baseline, with no tracking of changes over the follow-up period.

Research Recommendations
This short review raises the need for a systematic review of literature on this topic, however, it also allows us to make recommendations for practical research topics. We recommend that future studies specifically investigate the effects of antioxidants on vulnerable populations, such as children with asthma, the elderly, certain occupational workers and people with genetic susceptibility as these subpopulations may benefit the most from targeted dietary or supplemental interventions. Although several of the studies identified did focus on susceptible populations, it would be beneficial to expand the literature regarding those who experience increased responses to TRAP and specifically investigate genetic susceptibilities possibly in different ethnic populations. In the included studies, many participants were generally healthy adults. While healthy adults are also at risk of the adverse effects of TRAP, young and healthy adults may be more likely to consume better foods and be more active than the general population, which could influence exposure and response to pollutants and antioxidants [46]. Furthermore, this review warrants more detailed research regarding the role that obesity may play in the adverse health effects associated with TRAP. Obesity continues to be a major threat to health and contributes to other TRAP health effects listed in this review, such as asthma [77]. A vulnerable population that has not been discussed in the literature is lower socioeconomic status individuals. These populations exhibit a variety of factors which might heighten their risk of adverse health effects from TRAP exposures, including exposure to violence, stress, reduced access to health care and poor diet [78]. Additionally, there is a need for further investigation on the effective dose of antioxidant supplements, as well as a greater insight into reasons for conflicting results regarding the effectiveness of different antioxidant diets (e.g., fish oil and olive oil). Future research would also benefit from control for confounding effects from daily dietary intakes and changes in diet over follow-up. It should be noted that curcumin, an Asian spice that has antioxidant properties, was not included in this review. A meta-analysis suggests that the antioxidant properties of curcumin could mitigate depressive and anxiety symptoms in patients [79]. Therefore, future research could be aimed at investigating the potential for curcumin to mitigate the burden of disease caused by TRAP. Finally, more research could be undertaken to evaluate the potential of antioxidants in mitigating air pollution effects in other organs or diseases of the body than were discussed in this paper.

Policy Recommendations
Policy makers should continue to pursue legislation that would reduce levels of TRAP. In 2016, 91% of the world's population still lived in areas that exceeded the World Health Organization air quality guideline values [80], which are even too high to fully protect public health. However, until the long-term goal of cleaning the air can be met, policy makers could consider the use of antioxidant-rich diets, and to a lesser extent supplements, as a means of mitigating adverse health effects associated with TRAP. For example, schools in highly polluted areas may be incentivized to serve lunches that are antioxidant rich. Simple changes to a school lunch menu could be serving oil rich and organic fish at least once a week and increasing the organic fruits and vegetables at every meal. Furthermore, nursing homes and other care facilities for older adults should consider employing the use of antioxidant-rich diets. In addition to the Mediterranean diet reducing inflammation and mitigating adverse health effects of TRAP, there is evidence that the Mediterranean diet supplemented with extra virgin olive oil and mixed nuts can reduce age related cognitive decline in the elderly [81]. Such evidence might be applicable to the increasing body of evidence showing that air pollution, and TRAP specifically, is linked to cognitive decline [33][34][35]82]. It is important to address TRAP in particular as vehicles are one of the major sources of ambient air pollution, which specifically act in close proximity to an increasing proportion of people, thus making the adverse impacts of TRAP exposure widespread [78,80].

Practice Recommendations
Clinicians and health practitioners should encourage their clients to consume an antioxidant-rich diet and increase their organic fruit and vegetable intake, especially for children, elderly, pregnant women, and asthmatics. A cost-effective population-based intervention would be to bring awareness to the importance of dietary practices. Furthermore, occupations that are chronically exposed to TRAP, such as construction workers, transportation workers, and street vendors, should recommend or incentivize their employees to increase their nutritional or supplemental antioxidant intake. Raising awareness in dietary health benefits can be provided relatively easily, for little cost and in a manner that goes hand-in-hand with improving education for all on the health risks of air pollution.

Conclusions
Antioxidants may reduce the effects of oxidative stress because they can remove oxidizing agents and inhibit oxidation. Because of this, an antioxidant-rich diet or antioxidant supplement intake can potentially be used as a preventive strategy for the harmful health effects of TRAP. In this literature review, we identified 11 papers in the last 15 years that considered the potential benefits of increased antioxidant intake through diet or supplementation on mitigating the adverse health effects of exposure to common traffic-related air pollutants. Antioxidant interventions investigated ranged from adherence to the Mediterranean diet, increased fruit and vegetable intake, consumption of fish oil and olive oil, sulforaphane intake via broccoli sprout beverages, and vitamin C and E supplements. Major points to note from the literature include fruit and vegetable rich diets, the Mediterranean diet, fish oils and vitamin C and vitamin E provide protection from the adverse health effects associated with TRAP. Greater adherence to a diet rich in fruits and vegetables or the Mediterranean diet was effective in reducing the adverse health effects associated with TRAP and had no negative effects associated with them. While there are inevitably inconsistencies in the findings, the overall weight of evidence suggest that antioxidant intake can ameliorate the effects of TRAP in different organ systems. There is good evidence to recommend that healthy and susceptible individuals should practice greater adherence to the Mediterranean diet and increase their fruit and vegetable intake. There is conflicting evidence regarding the use of antioxidant supplements and thus a need for more research focusing on antioxidant supplementation. Future research should focus on conducting cohort studies to analyze long-term effectiveness of antioxidants in studies that are representative of real-world exposures and with better control for confounders. Given the near ubiquitous exposure to pollution worldwide, and the huge impact on health, these findings have relevance to the general public, but also to health practitioners, clinicians, employers and policymakers seeking to limit the burden of air pollution on health. Specifically, susceptible populations including asthmatics, elderly and those with genetic variations should increase their antioxidant intake in order to attenuate the adverse health effects associated with air pollution and TRAP exposures. In conclusion, until lower levels of TRAP are achieved, antioxidant-rich diets and supplementation may offer promise for reducing the burden of disease associated with TRAP exposures.

Conflicts of Interest:
None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.