Health effects research and regulation of diesel exhaust: an historical overview focused on lung cancer risk

Figures & data

Table 1.  Key regulatory actions affecting diesel engine exhaust in the United States.

Year	Event
1968	First “smoke standard” promulgated in the US for onroad HDDE (33 FR 8304, June 4, 1968)
1970	Clean Air Act of 1970 provide US EPA with authority to issue National Ambient Air Quality Standards (NAAQS), as well as provisions for regulating diesel engines and fuels. (42 U.S.C. §7401 et seq. (1970))
1971	Issuance of initial NAAQS for criteria air pollutants (PM, CO, NOx, SO2, HC, and O3) (36 FR 8186, April 30, 1971)
1974	US EPA implementation of first US CO standard and a combined HC and NOx standard for onroad HDDE
1977	US EPA issues precautionary notice of the mutagenicity of organic solvent assays of diesel exhaust particles in bacterial assays (November 4, 1977)
1979	US EPA, along with the US Department of Energy and the Department of Transportation, request that the National Research Council conduct an evaluation of the potential health impacts associated with prospective widespread use of diesel-powered light-duty vehicles in the United States
	US EPA implementation of new HC standard for on-road HDDE (while retaining the combined HC+NOx standard)
1982	US EPA introduction of first on-road diesel engine PM emissions standard (light-duty diesel cars and trucks, but not HDDE) (45 FR 14496, March 5, 1980)
1985	US EPA implementation of new NOx standard (10.7 g/bhp-hr) for on-road HDDE, and elimination of combined HC+NOx standard. (50 FR 10606, March 15, 1985)
1987	US EPA reduces PM standards to 0.2 g/mile and 0.26 g/mile for light-duty diesel cars and trucks, respectively (47 FR 54250, December 1, 1982)
	US EPA replaces TSP-based PM NAAQS with PM10 standards (52 FR 24634, July 1, 1987)
1988	US EPA introduction of first PM standard for on-road HDDE (0.6 g/bhp-hr)
1990	State of California, under the Safe Drinking Water and Toxic Enforcement Act of 1986 (Proposition 65) identifies diesel exhaust as a chemical “known to the State to cause cancer”
	US EPA implements reduced on-road HDDE NOx standard of 6.0 g/bhp-hr
1991	US EPA implements reduced PM standard of 0.25 g/bhp-hr for HDDE in trucks and urban buses
	US EPA implements reduced on-road HDDE NOx standard of 5.0 g/bhp-hr
1993	US EPA implements reduced PM standard of 0.1 g/bhp-hr for HDDE in urban buses
	US EPA regulations for sulfur (500 ppm limit) and aromatic hydrocarbons (no more than 35% by weight) in highway diesel fuel go into effect
1994	US EPA implements reduced PM standards of 0.1 g/bhp-hr and 0.07 g/bhp-hr for on-road HDDE in trucks and urban buses, respectively
	US EPA establishes first emissions standards (Tier 1 emissions standards for CO, HC, PM, NOx, and smoke emissions) for non-road diesel engines at or above 37 kW (59 FR 48472, September 21, 1994)
	US EPA Tier 1 standards for light-duty vehicles go into effect, with a phase-in implementation schedule of 1994–1997
1996	US EPA implements reduced PM standard of 0.05 g/bhp-hr for on-road HDDE in urban buses
1997	US EPA finalizes rulemaking establishing new emission standards for model year 2004 and later truck and bus HDDE, targeting NOx and non-methane hydrocarbons (NMHC) using two alternative standards (either a combined NOx+NMHC limit of 2.4 g/bhp-hr, or a NOx limit of 2.5 g/bhp-hr and a NMHC limit of 0.5 g/bhp-hr) (62 FR 54694, October 21, 1997)
	US EPA issues first fine particulate matter (PM2.5) NAAQS (62 FR 38652, July 18, 1997)
1998	US EPA implements reduced NOx standard of 4.0 g/bhp-hr for all on-road HDDE
	US EPA finalizes first emission standards for locomotives and puts in place a three-tiered system for regulating engines manufactured between 1973 to 2001, 2002 to 2004, and post-2005 beginning in 2000 (63 FR 18978, April 16, 1998)
	US EPA finalizes more stringent emission standards (Tiers 2 and 3) for NOx, HC, and PM from new non-road diesel engines, including the first set of standards for non-road diesel engines below 37 kW. (63 FR 56967, October 23, 1998)
1999	US EPA issues first emissions standards for commercial marine diesel engines at or above 37 kW, establishing Tier 1 (voluntary NOx approach) and Tier 2 (for combined HC + NOx, PM, and CO) emission standards for new Category 1 and 2 marine diesel engines smaller than 30 liters per cylinder. (64 FR 73300, December 29, 1999)
2000	US EPA promulgates the first emission standards for marine diesel engines to take effect between 2004 and 2007 (Proposed Rule – 65 FR 76797 – December 7, 2000)
	US EPA lists diesel exhaust as a “mobile source air toxic”
2001	US EPA finalizes the “2007 Heavy-Duty Highway Rule,” establishing updated emission standards for 2004 and later heavy-duty highway engines and vehicles and highway diesel fuel sulfur control requirements (ultra-low sulfur diesel fuel with sulfur levels at or below 15 ppm) (66 FR 5002, January 18, 2001)
	MSHA publishes final rule establishing DPM concentration limits (interim concentration of 400 μg of total carbon per m^3 to go into effect in July 2002, and a final concentration limit of 160 μg of total carbon per m^3 to go into effect in January 2006) for underground metal and non-metal miners (66 FR 5706, January 19, 2001)
2002	US EPA finalizes first emissions standards (for combined HC + NOx, PM, and CO) for recreational marine diesel engines over 37 kW (67 FR 68242, November 8, 2002)
2003	US EPA issues final rule establishing near-term, Tier 1 emission standards for NOx for new (2004 and later) commercial marine diesel engines (Categories 1, 2, and 3) that will be installed on vessels flagged or registered in the United States (68 FR 9746, February 28, 2003)
2004	US EPA adopts Clean Air Nonroad Diesel Final Rule, putting in place a comprehensive program to reduce NOx and PM emissions by more than 90 percent from non-road diesel engines that includes Tier 4 emissions standards and the first regulations to reduce the allowable sulfur content (by more than 99 percent) in diesel fuels used in non-road diesel engines, locomotives, and marine vessels (68 FR 38958 – June 29, 2004)
	1997 NOx/NMHC HDDE emissions standards go into effect (62 FR 54694, October 21, 1997)
	US EPA Tier 2 standards for light-duty vehicles go into effect, tightening the previous Tier 1 emissions limits and establishing consistent emission standards regardless of vehicle weight and fuel type, with a phase-in implementation schedule of 2004–2009 (see 1998)
2005	MSHA issues final rule with revisions to its DPM concentration limits for underground metal and non-metal miners, replacing the interim DPM concentration limit with a permissible exposure limit (PEL) of 308 μg/m^3 measured as elemental carbon (70 FR 32868, June 6, 2005)
2006	Effective year of US EPA’s 2001 standard for highway ultra-low sulfur (15 ppm) diesel fuel (ULSD) (66 FR 5002, January 18, 2001)
	MSHA publishes a final rule phasing in the DPM final concentration limit of 160 (Total Carbon) μg/m^3 over a two-year period based on feasibility, with a final compliance date of May 20, 2008 (71 FR 28924, May 18, 2006)
	US EPA reduces the 24-h PM2.5 NAAQS from 65 μg/m^3 to 35 μg/m^3 (71 FR 61144, October 17, 2006)
2007	US EPA 2001 PM emissions standard for new heavy-duty engines of 0.01 g/bhp-hr goes into effect; beginning of phase-in of updated standards for NOx and NMHC of 0.20 g/bhp-hr and 0.14 g/bhp-hr (see 2001)
	Non-road diesel engines, including locomotives and smaller marine engines, now required to use low sulfur (500 ppm) diesel fuel (see 2004)
2008	US EPA finalizes more stringent emissions standards for locomotives and marine diesel engines, including Tier 3 and Tier 4 standards intended to reduce PM and NOx emissions by 80–90% and the first national emission standards for existing marine diesel engines (73 FR 25098, May 6, 2008)
2010	US EPA 2001 updated NOx and NMHC emissions standards to be in full effect (see 2001)
	US EPA finalizes rule adding two new tiers of Category 3 (C3) marine diesel engine emission standards (Tier 2 and Tier 3 standards for NOx, HC, and CO) and revising its standards for marine diesel fuels produced and distributed in the United States (75 FR 22896, April 30, 2010)
	Effective year for requirement that non-road diesel engines use ultra-low sulfur (15 ppm) diesel fuel (see 2004)
2012	Effective year for requirement that locomotives and smaller marine engines use ultra-low sulfur (15 ppm) diesel fuel (see 2004)

Notes: For those regulatory activities where specific regulatory citations could not be identified, US EPA (1997, 2002) are the information sources.

Figure 1.  Evolution of US heavy-duty diesel engine on-road emissions standards, expressed as grams PM or NO_x emitted per brake-horsepower-hour (g/bhp-hr). Note that in 2004 two alternative standards were implemented: either a combined NO_x+NMHC limit of 2.4 g/bhp-hr, or a NO_x limit of 2.5 g/bhp-hr and a NMHC limit of 0.5 g/bhp-hr. See Table 1 for additional details and citations for the emissions standards.

Figure 2.  Chemical compositions of PM in NTDE (data from Khalek et al., 2011; based on averaged data for four 2007-model-year heavy-duty diesel engines, including three equipped with a diesel oxidation catalyst (DOC) and a catalyzed diesel particulate filter (c-DPF), and engine equipped with an exhaust diesel fuel burner and c-DPF) versus TDE (data from US EPA, 2002; for 1990s-era diesel engine technology) from heavy-duty diesel engines. PM mass emissions bars for NTDE and TDE derived from data compiled in Hesterberg et al. (2008) for diesel school buses with and without catalyzed DPFs (used in conjunction with ULSD), respectively. Note that there can be variability in PM emissions for diesel engine technologies considered to emit NTDE and TDE, such that data from other studies may differ from those in the figure. In general, as illustrated in these comparisons, not only is less PM emitted in NTDE on a per mile basis, but the emitted PM differs in composition from the PM emitted in TDE.

Figure 3.  Average % reductions for DEP chemical classes relative to 2004 diesel technology engines for ACES testing of four post-2006 technology diesel engines (data from Khalek et al., 2011). ACES testing for 12 repeats of 16-h transient cycle developed at West Virginia University that covers a complete engine operation with active regeneration events. *Reductions in dioxins/furans are for comparison with 1998 technology engines.

Figure 4.  Average particle number emissions (note the logarithmic scale) for 2007 ACES engines (with and without c-DPF regeneration) versus a 2004 technology engine. As discussed in Khalek et al. (2011), data for the 2007 ACES engines were based on 12 repeats of the 20-min federal test procedure transient cycle (FTP) or 12 repeats of the 16-h cycle, each for all four ACES engines and for sampling from an unoccupied animal exposure chamber set up on a constant volume sampler (CVS). Data for the 2004 technology engine were based on six repeats of the FTP transient cycle from a full flow CVS. All data are reported on a brake-specific emissions basis, which is defined by Khalek et al. (2011) as the total emissions during a test interval over the work expressed in brake horsepower-hour.

Table 2.  Overview of reported exposure levels for DE-exposed worker groups and the general population based on EC measurements and predicted DEP concentrations.

Population	DEP indicator	Average concentration (μg/m^3)	Reference/comments
General population (ambient air)	DEP	0.06–2.95	US EPA (2011) – Range of modeled statewide averages for 2005 emissions inventory
Truck drivers–local	EC	2–7	Pronk et al. (2009) – Range of measured AMs from four studies
	EC	1.0 (cold), 1.2 (warm)	Davis et al. (2011) – Measured GMs for 2001–2006 TrIPS data
Truck drivers–long haul	EC	1–22	Pronk et al. (2009) – Range of measured AMs from four studies
	EC	1.1	Davis et al. (2011) – Measured GM for 2001–2006 TrIPS data
Bus drivers	EC	2–11	Pronk et al. (2009) – Range of measured AMs from four studies
Mechanics in truck terminals, bus garages, stand-alone maintenance shops	EC	4–39	Pronk et al. (2009) – Range of measured AMs from seven studies
	EC	4.3 (cold), 1.5 (warm)	Davis et al. (2011) – Measured GMs for 2001–2006 TrIPS data
Train crew	EC	4–20	Pronk et al. (2009) – Range of measured AMs from five studies
Railroad maintenance	EC	5–39	Pronk et al. (2009) – Range of measured AMs from two studies
Underground mine production workers	EC	148–637	Pronk et al. (2009) – Range of measured AMs from seven studies of various mine types (coal, metal, and non-metal)
Underground mine maintenance workers	EC	53–144	Pronk et al. (2009) – Range of measured AMs from two studies of nonmetal mines
Surface mine workers	EC	13–23	Pronk et al. (2009) – Range of measured AMs from two studies of nonmetal mines
Dockworkers	EC	4–122	Pronk et al. (2009) – Range of measured AMs from six studies
	EC	0.9	Davis et al. (2011)- Measured GM for 2001–2006 TrIPS data where propane-powered forklifts were dominant

Notes: DEP, diesel exhaust particulate; EC, elemental carbon; AM, arithmetic mean; GM, geometric mean.

EC means from Pronk et al. (2009) are for measurements using several different types of size-selective samplers (submicron, respiratory, inhalable, and not indicated). Although not shown in this table, Pronk et al. (2009) also compiled occupational exposure measurements collected using other exposure surrogates, including respirable PM, NO, NO₂, and CO. As indicated above, Davis et al. (2011) reported separate GMs for cold- and warm-weather conditions for local truck drivers and mechanics.

Figure 5.  Median predicted shift-level elemental carbon (EC) concentrations for trucking industry workers by decade (1971–1980, 1981–1990, 1991–2000), as reported in Davis et al. (2011). Job-specific concentrations are summarized, with multiple predictions for dockworkers corresponding to use of diesel-powered, propane-powered, and gasoline-powered forklifts and separate predictions for both mechanics and pickup & delivery drivers in warm versus cold climates. As discussed in Davis et al. (2011), their modeling analysis provides evidence of substantial reductions in truckers’ DE exposures over the last three decades. LH stands for long-haul, while P&D stands for pickup-and-delivery.

Figure 6.  Histogram of predicted annual county-average ambient diesel particulate matter (DPM) concentrations for the US EPA National-Scale Air Toxics Assessment (NATA) modeling analyses of 1996 and 2005 year air pollutant emissions (data from US EPA, 2011). DPM emissions include both on-road and non-road emissions sources. County numbers (out of 3191 counties for the 1996 emission year modeling and 3221 counties for the 2005 emission year modeling; both including municipalities in Puerto Rico and counties in the US Virgin Islands) are provided above each bar. These data suggest a decline in ambient DE exposure levels between 1996 and 2005, although there have also been improvements in NATA methods (e.g. inventory improvements, modeling changes, background calculation revisions) over time that may affect the interpretation of any differences between the two NATA analyses.

Table 3.  Timeline of key DE health effects research milestones.

Year	Event
1955	Kotin et al. (1954, 1955) publish first evidence of carcinogenicity of DE soot extracts based on mouse skin assay
Mid- to late 1950s	Hueper (1956), Raffle (1957), and Kaplan (1959) publish earliest epidemiologic analyses of lung cancer rates among railroad workers with diesel exhaust exposure, reporting conflicting findings
1978	Using bacterial assays (Ames Test), Huisingh et al. (1978) report first evidence of mutagenicity of organic extracts of DE soot
1979	1st US EPA international symposium on the health effects of diesel engine emissions held in December in Cincinnati, OH
1980	Health Effects Institute (HEI) formed as a nonprofit organization to help develop a database on the health effects of pollutants from motor vehicles and other environmental sources
1981	National Research Council (NRC) releases report “Health Effects of Exposure to Diesel Exhaust,” authored by the Health Effects Panel of NRC’s Diesel Impacts Study Committee; 2 US EPA diesel emissions symposium held in October in Raleigh, NC
1982	Symposium on Biological Tests in the Evaluation of Mutagenicity and Carcinogenicity of Air Pollutants with Special Reference to Motor Exhausts and Coal Combustion Products held in February in Stockholm, Sweden
Early 1980s	Flurry of studies (e.g. Brooks et al., 1984; Clark et al., 1981, 1984; Claxton, 1981, 1983; Lewtas, 1982, 1983; Siak et al., 1981) confirm mutagenicity of DPM extracts in bacterial and mammalian cells assays, showing large variability in mutagenic potency of soot extracts depending on such factors as engine, fuel type, operating conditions; early focus on potential health impacts of organic chemical constituents of DE
Early to mid-1980s	Early retrospective mortality cohort studies of occupational DE exposures and lung cancer (e.g. Waller, 1981; Howe et al., 1983; Rushton et al., 1983; Wong et al., 1985; Gustafsson et al., 1986)
1983	Zamora et al. (1983) report evidence that components of diesel extract act as weak tumor promoters
1986	International Satellite Symposium on Toxicological Effects of Emissions from Diesel Engines held in July in Tsukuba Science City, Japan
1986–1987	Early development of lung overload concept – Vostal (1986) proposes hypothesis that lung tumor development in rats exposed to highly elevated DE concentrations is due to consequences of lung overload in rats; Wolff et al. (1987) publish key paper developing concept of lung overload
Mid- to late 1980s	Initial series of findings from large-scale (50 or more animals per group) chronic inhalation DE carcinogenicity bioassays (e.g. Heinrich et al., 1986; Mauderly et al., 1986, 1987; Takemoto et al., 1986; Ishihara, 1988; Brightwell et al., 1989; Lewis et al., 1989); additional epidemiological studies published, including early analyses of US railroad workers (Garshick et al., 1987, 1988) and large general population cohorts (Boffetta et al., 1988; Boffetta and Stellman, 1988)
Early 1990s	US EPA releases first draft of its “Health Assessment Document for Diesel Engine Exhaust”; first studies of DE exposures and lung cancer risks of Teamsters Union trucking industry workers published (Steenland et al., 1990, 1992; Zaebst et al., 1991)
1995	Health Effects Institute’s (HEI’s) Diesel Working Group releases special report “Diesel Exhaust: A Critical Analysis of Emissions, Exposure, and Health Effects,” which includes critical review of all published epidemiologic studies available through June 1993 bearing on the lung cancer risk posed by occupational DE exposure (35 in total); Massachusetts Institute of Technology (MIT) Toxicology Symposium “Particle Overload in the Rat Lung and Lung Cancer: Relevance for Human Risk Assessment” held in Cambridge, MA
1995–1996	Second wave of published findings for chronic inhalation carcinogenicity bioassays with groups of 50 or more animals (e.g. Heinrich et al., 1995; Nikula et al., 1995; Mauderly et al., 1996)
Mid- to late 1990s	Emerging consensus that findings of rat lung tumors at highly-elevated DE exposure levels are due to non-specific response to a high lung burden of particles (i.e. lung overload) rather than response to specific DE mutagens (e.g. PAHs, nitro-PAHs), and that rat findings may be of little relevance to human lung cancer risk from environmental DE exposures (Oberdörster, 1995; Mauderly, 1996, 1997, 2000; Mauderly and McCunney, 1996; Valberg and Crouch, 1999; ILSI, 2000; US EPA, 2002)
Mid-1990s to mid-2000s	Burgeoning number of literature reviews addressing the health effects evidence for DE and lung cancer risk, including Mauderly (1994), HEI (1995), Muscat and Wynder (1995), IPCS (1996), Stöber and Abel (1996), Morgan et al. (1997), Stöber et al. (1998), Lloyd and Cackette (2001), US EPA (2002); Bunn et al. (2004), Hesterberg et al. (2005, 2006)
1997–1999	Early meta-analyses (e.g. Bhatia et al., 1998; Lipsett and Campleman, 1999) and re-analyses of epidemiologic data (e.g. Cox 1997; Cal EPA, 1998; Crump, 1999) bearing on occupational DE exposure and lung cancer risk
1998	Updated Teamsters Union epidemiological study published (Steenland et al., 1998)
1999	HEI’s Diesel Epidemiology Expert Panel releases report “Diesel Emissions and Lung Cancer: Epidemiology and Quantitative Risk Assessment” that concludes that reliable epidemiologic data are not currently available to support a quantitative risk assessment for DE exposure and lung cancer risk; meta-analysis of chronic inhalation carcinogenicity bioassay data published by Valberg and Crouch (1999)
Late 1990s-present	Periodic publication of additional cohort (Saverin et al., 1999; Jarvholm and Silverman, 2003; Neumeyer-Gromen et al., 2009) and population-based case–control epidemiological studies of occupational DE exposure and lung cancer risk (e.g. Bruske-Hohlfeld et al., 1999; Gustavsson et al., 2000; Boffetta et al., 2001; Soll-Johanning et al., 2003; Guo et al., 2004; Richiardi et al., 2006; Parent et al., 2007; Villeneuve et al., 2011); Increasing number of ambient air pollution epidemiological studies reporting associations between exposure to traffic-related air pollution and adverse health outcomes, including asthma exacerbation, cardiovascular and respiratory morbidity, and premature mortality (recently reviewed in HEI, 2010)
~2000	Approximate time-period of shift in DE health effects research from predominant focus on lung cancer risk to broad range of potential non-cancer health hazards (Mauderly and Garshick, 2009)
2002	US EPA releases final “Health Assessment Document for Diesel Engine Exhaust”; HEI Diesel Epidemiology Working Group releases special report “Research Directions to Improve Estimates of Human Exposure and Risk from Diesel Exhaust” that recommended a series of short-term, medium-term, and long-term research activities intended to enhance the epidemiologic evidence addressing disease risks associated with diesel emissions
2003	Workshop, jointly organized by HEI and CRC, held in Denver, Colorado, to begin the process of developing an approach and guidelines for ACES emissions characterization and health effects evaluation
2004–2006	Updates published for US railroad worker cohort with increased years of follow-up and refinements to models and exposure assessment (e.g. Garshick et al., 2004, 2006; Lee et al., 2004; Laden et al., 2006)
2005	Hesterberg et al. (2005) propose the term “New Technology Diesel Exhaust (NTDE)” to differentiate the exhaust from post-2006 advanced diesel engines with integrated, multi-component emissions reduction systems (modern electronic fuel injection systems, ultra-low-sulfur fuel, special lubricants, and exhaust aftertreatment devices such as diesel particulate filters) with DE from pre-2006 diesel engines; Stinn et al. (2005) publish most recent chronic inhalation carcinogenicity bioassay with groups of 50 or more animals
Mid-2000s to present	Series of exposure assessment studies (Lee et al., 2005; Smith et al., 2006; Davis et al., 2006, 2007a, 2007b, 2011; Sheesley et al., 2008, 2009) and epidemiologic studies (Laden et al., 2007; Garshick et al., 2008) published by researchers at the Harvard School of Public Health as part of National Cancer Institute funded cohort study of lung cancer in the US trucking industry
2007	Beginning of ACES emissions and toxicological testing of exhaust from new technology diesel engines meeting the 2007/2010 emissions standards
2010	Series of studies published detailing the estimation of historical DE exposures among workers at underground non-metal mining facilities (Stewart et al., 2010; Coble et al., 2010; Vermeulen et al., 2010a, 2010b)
2010–2011	Recent critical reviews and re-analyses of epidemiological data for historical occupational DE exposure and lung cancer risk (e.g. Gamble, 2010; Olsson et al., 2011a)
2012	Epidemiology papers published for NIOSH-NCI Diesel Exhaust in Miners Study (DEMS), including a cohort mortality study (Attfield et al., 2012) and a nested case–control study of lung cancer mortality (Silverman et al., 2012), each conducted for DE-exposed miners at eight US non-metal mining facilities
2013	Final reports expected detailing the findings of the ACES chronic inhalation bioassays for exhaust from new technology diesel engines meeting the 2007/2010 emissions standards

Table 4.  Summary of recent (post-US EPA Diesel HAD, 2001 and later) epidemiological studies of DE-lung cancer risk.

CE, cumulative exposure; CI, confidence intervals; D-JSM, diesel job-specific modules; EC, elemental carbon; E-R, exposure-response; JEM, job-exposure matrix; LH, long-haul;

OR, odds ratio; P&D, pick-up and delivery; RR, relative risk; SIR, standardized incidence ratio; SMR, standardized mortality ratio; TC, total carbon.

Figure 7.  Chart shows study-specific and overall pooled-study lung-cancer odds ratios (OR) and 95% confidence intervals (CIs) for the highest quartile of cumulative diesel exhaust exposure compared with never-exposed, adjusted for age, sex, cigarette pack-years, time-since-quitting smoking, and ever-employment in a “List A” job (from Olsson et al., 2011a). Studies are identified by locations, with study acronyms provided in parentheses. As summarized in our Table 4,Olsson et al. (2011a) pooled information from 11 European and Canadian case–control studies covering 13,304 cases, with exposures typically between the 1920s/1930s and the 1990s/2000s. As noted inOlsson et al. (2011a), the symbol size reflects weighting from the random effects analysis. For global testing of the heterogeneity between the study ORs,Olsson et al. (2011a) reported an overall I-squared (I²) of 13.8% (p = 0.292) and concluded that there was no significant heterogeneity.

Figure 8.  Possible mechanistic pathways leading to lung tumors in rats exposed by inhalation to protracted, high concentrations of poorly-soluble particles (adapted from Hesterberg et al., 2005 and HEI, 1995).

Figure 9.  Impaired lung clearance in rats of ¹³⁴Cs-radiolabeled particles inhaled after the end of 24-months DE exposure (for high, medium, and low DE exposure concentrations of 7.0, 3.5, and 0.35 μg/m³, respectively) and for a control population (0 mg/m³ DE exposure). Data points are means ± standard errors (SEs). From Wolff et al. (1987).

Figure 10.  Relationship of normalized weekly exposure of rats to DEP versus rat lung tumor response (adapted from Mauderly and Garshick, 2009). Data from nine published studies with groups of 50 or more rats exposed ≥24 months to DE; data from the single chronic rat study published since the 1988 IARC DE review – Stinn et al. (2005) – are specifically labeled. Lung tumor increases are shown (exposed minus controls). Dashed line represents control incidence (no net increase). Open circles represent exposed groups with no statistically significant increase above the control incidence. Closed circles represent exposed groups with a statistically significant increase above individual control group lung tumor incidence. In addition to the DEP study data, we have also plotted data for carbon black (CB) from Nikula et al. (1995). Although Heinrich et al. (1995) also included a CB exposure group and observed a 27% excess in lung tumor incidence (exposed minus controls), we did not include this data point in the figure since the weekly exposure rate of 990 mg-h/m³ is well outside the range of DEP exposure rates and would have thus distorted the figure scale.

Table 5.  Summary of pulmonary effects in different species related to high particle load (from Oberdörster, 1995).

Pulmonary effect	Rat	Mouse	Hamster	Evidence in coal workers^a
Prolonged particle clearance	++	++	++	[X]
Inflammation	++	+	(+)	X
Cell proliferation	++	+	(+)	X
Fibrotic foci	++	+/−	(+)	X
Localized emphysema	+	−	(−)	X
Tumors	++	−	−	−

Notes: Overall response to highly-insoluble, low-toxicity particles: rats>mice>hamsters; rats>primates (?).

The use of () for the hamster indicate that response is present but weaker than that observed for the rat and/or mouse.

^aThe evidence in coal workers (X) is not meant as a quantitative comparison to the three rodent species but merely indicates that a given adverse response has been observed in these workers. As detailed in the text, indirect evidence ([X]) in coal workers for prolonged lung clearance comes from studies by Freedman and Robinson (1988), Freedman et al. (1988), and Stöber et al. (1965).

Figure 11.  Summary of McDonald et al. (2004b) findings on the relative toxicity in mice of acute inhalation exposures (6 h per day over 7 days) for a baseline uncontrolled, TDE emissions case (approximately 200 μg/m³ DEP) versus an emissions reduction case (low-sulfur fuel, catalyzed ceramic trap, 7 μg/m³). Expressed as relative responses to filtered air, findings are shown for four indicators of acute lung toxicity, namely respiratory syncytial virus (RSV) resistance, histopathology, lung inflammation (specifically, measurements of tumor necrosis factor-α (TNF-α)), and oxidative stress.

Figure 12.  Comparison of total PM emissions (on a mass per-distance-traveled basis) and PM composition for light-duty automobile engine exhausts representative of TDE, NTDE, and GEE. All data based on particle composition measurements from Cheung et al. (2009), who conducted emissions testing on a chassis dynamometer for light-duty vehicles operated using different aftertreatment configurations and a cold-start New European Driving Cycle (NEDC) and a series of Artemis cycles. Specific vehicle configurations include a Euro 4+ Honda Accord (2.2 L, i-CDTi) equipped with a ceramic-catalyzed diesel particulate filter (c-DPF), a closed-coupled oxidation catalyst (pre-cat), and exhaust gas recirculation (EGR), operated using low sulfur (<10 ppm) diesel fuel and lube oil with a sulfur content of 8900 ppm wt (considered to be NTDE); a Euro 3 Toyota Corolla (1.8 L) equipped with a three-way catalytic converter and operated using unleaded gasoline with a research octane number (RON) of 95 and fully synthetic lube oil (considered to be GEE); and a Euro 1 compliant Volkswagen Golf (TDI, 1.9 L) operated using diesel fuel with a nominal sulfur content of 50 ppm (considered to be TDE).

Table 6.  Summary of DE/DEP hazard assessments conducted by regulatory agencies and authoritative bodies.

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