1 March 31, 2012

John Howard, M.D. Administrator, World Trade Center Health Program Centers for Disease Control and Prevention (CDC) National Institute for Occupational Safety and Health (NIOSH) 395 E. St, S.W. Suite 9200, Patriots Plaza Washington, D.C. 20201

Dear Dr. Howard: We are writing in response to your letter of October 5, 2011 requesting advice from the World Trade Center (WTC) Health Program Scientific/Technical Advisory Committee (STAC) on whether to add cancer, or a certain type of cance r, to the List of World Trade Center (WTC)

- Related Health Conditions in the James Zadroga Act (“List”). The STAC has reviewed available information on cancer outcomes that may be associated with the exposures resulting from the September 11, 2001 terrorist attacks, and believes that exposures resulting from the collapse of the buildings and high

- temperature fires are likely to i ncrease the probability of developing some cancers. This conclusion is based primarily on the presence of approximately 70 known an d potential carcinogens in the smoke, dust, volatile and semi

- volatile

c ontaminants identified at the World Trade Center s ite (Table 1 ). Fifteen of these substances are classified by the International Agency for Research on Cancer (IARC) as known to cause cancer in humans , and 37 are classified by the National Toxicology Program (NTP) as reasonably anticipated to cause cancer in humans ; others are classified by IARC as probable and possible carcinogens

. Many of the se carcinogens are genotoxic and it is ther efore assumed that any level of exposure carries some risk. Exposure data are extremely limited

. No data were collected in the first 4 days after the attacks, when the highest levels of air contaminants occured, and the variety of samples taken on or afte r September 16, 2001 are insufficient to provide quantitative estimates of exposure on an individual or area level. However, t he committee considers that the high prevalence of acute symptoms and chronic conditions observed in large numbers of rescue, reco very, clean up and restoration workers and survivors, as well as qualitative descriptions of exposure conditions in downtown Manhattan , represent highly credible evidence that significant toxic exposures occurred. Furthermore, the salient biological
reacti on that underlies many currently recognized WTC health conditions

— persistent inflammation

— is now believed to be an important mechanism underlying cancer through generating DNA

- reactive substances, increasing cell turnover, and releasing biologically active substances that promote tumor2

growth, invasion and metastasis. Given that cancer latencies for solid tumors average 20 years or more, it is noteworthy that the published FDNY study of fire fighters showed a statistically significant excess in all

- site can cer with only 7 years of follow

- up. The committee deliberated on whether to designate all cancers as WTC

- related conditions or to list only cancers with the strongest evidence. S ome members propos ed to include all cancers based on the incomplete and limit ed epidemiological data available to identify specific cancers, and others argued for the alternative of listing specific cancers based on best available evidence

. The committee agreed to proceed by generat ing a list of cancers potentially related to WTC e xposures based on evidence from

t hree sources described below : (1) cancer s with limited or sufficient evidence in humans based on the International Agency for Research (IARC) Monographs reviews for carcinogens present at the WTC site (Table 2 ); (2) cance rs arising in regions of the respiratory and digestive tracts where WTC

- related inflammatory conditions have been documented (Table 3 ); and (3) cancer s for which epidemiologic studies have found some evidence of increased risk in WTC responder and survivo r populations (Table 4 ). The organ sites identified from any of the three sources are listed in Table 4

. The committee reviewed the evidence summarized for each organ site or site grouping in Table 4 to develop its recommendation on which sites should be l isted as WTC

- related conditions. In addition, the committee considered the evidence for inclusion of several sites that were not identified from Table 4

. The committee recommends listing the following site grouping s and sites as WTC

- related conditions base d on the strength of the evidence summarized in Table 4 and/or additional information provided below.

 The committee recommends that malignant neoplasms of the respiratory system ( including n ose, nasal cavity and middle ear ( ICD

- O

- 3 site codes C300

- C301, C 310

- 319) , larynx C320

- C329) , lung and bronchus (CC340

- C349) , pleura (C384) , trachea, mediastinum and other respiratory organs (C339,
C381

- C383, C388, C390, C398, C399) ) be listed as WTC

- related conditions. These cancers are associated with exposure to many carcinogenic agents of concern at the WTC , including arsenic, asbestos, beryllium, cadmium, chromium, nickel, silica dust and soot

. The respiratory tract is also the major site for acute and chronic toxicity resulting from WTC

- exposures , including chronic nasopharyngitis, upper airway hyperreactivity, chronic laryngitis, interstitial lung disease, “ chronic respiratory disorder

– fumes/vapors ” , reactive airways disease syndrome (RADS) and chronic cough syndrome

. Although the Zeig

- Owens study 1 did not find evidence for an increased risk of lung or3

other respiratory cancers among FDNY firefighters, both internal and external comparisons may have been affected by g reater declines in smoking among WTC

- exposed firefighters (due in part to their respiratory symptoms) than unexposed firefighters or the general public. Commendably, in 2002 a joint labor

- management initiative offered a comprehensive voluntary smoking cess ation program free of charge to FDNY smokers and family members 2

. S moking cessation reduces lung cancer rates within 5

– 10 years after quitting. Thus, any increased r isk of lung cancer associated with WTC exposures may have been obscured by lower rates of smoking

- related lung cancer.

 The committee recommends t hat certain cancers of the digestive system, including esophagus (C150

- C159), stomach (CC160

- C169), colon and rectum (C180

- 189, C260, C199, C209), liver and intrahepatic bile duct (C220

- CC221), retroperitoneum, peritoneum, omentum and mesentery (C48 0

- C 4 82 , C488 ) be listed as WTC

- related conditions. Esophag eal cancer is associated with tetrachloroethylene, stomach cancer is associated with asbestos and inorganic lead compounds , and colorectal cancer is associated with asbestos (Table 4 ). C ancer of the liver has been associated with vinyl chloride, arsenic and inorganic arsenic compounds, polychlorinated biphenyls, a nd trichloroethylene (Table 4 ). Gastrointestinal reflux disease (GERD) is associated with cancer of the esophagus, especially if it progresses to Barrett esophagus. Since cancer of the distal esophagus,
g astroesophageal junction and gastric cardia share co mmon risk factors, Table 4 shows GERD as a WTC

- related condition for stomach as well as esophageal cancer. The Zeig

- Owens study 1 found evidence of an increase d risk of stomach (including gastro

- esophageal junction) and colorectal

cancer among FDNY firefighters

.

 The committee recommends that c ancers of the oral cavity and pharynx, including lip (C000

- C009), tongue (C019

- C029), salivary gland (C079

- C089), floor of mouth (C040

- C049), gum and other mouth (C030

- C039, C050

- C059, C060

- C069), nasopharynx (C110

- C119) , tonsil (C090

- C099), oropharynx (C100

- C109), hypopharynx (C129, C130

- C 139) and other oral cavity and pharynx (C140

- C1 48 ) be listed as WTC

- related condition s. IARC has found limited evidence that asbestos causes pharyngeal cancer in humans and sufficient evidence that formaldehyde causes cancer of the nasopharynx. The lip, oral cavity and pharynx are areas with high potential for direct exposure to toxic mate rials through hand

- to

- mouth contact.

 The committee recommends that soft tissue sarcomas (C380, C470

- C479, C490

- C499) be listed as
WTC

- related conditions

. IARC has found limited evidence for increased risk of soft tissue sarcoma associated with exposure to polychorophenols and their sodium salts and 2,3,7,8

- TCDD. Soft tissue4

sarcoma rates are very low in the general population (age

- adjusted incidence rate approximately 3 per 100,000) and therefore excesses are difficult to detect in epidemiologic studies.

 The committee recommends that melanoma (C440

- 449) and non

- melanoma skin cancers (C440

- C449) , including scrotal cancer (C632) , be listed as WTC

- related conditions. According to IARC, s kin cancer is associated with exposure to arsenic and inorganic arsenic compounds and soot (Table 4 )

. The Zeig

- Owens study 1 found a statistically significant increase in mel an oma among exposed firefighters compared to the general population ; the Standardized Incidence Ratio (SIR) was slightly larger but not significant when compared to non

- exposed firefighters. No adjustment for surveillance bias was reported for malignant melanoma , although early detection through medical surveill ance is likely

.

 The committee recommends that mesothelioma (ICD

- O

- 3 histology 9050

- 9055) be listed as WTC

related condition s

. Asbestos exposure is the only known cause of mesothelioma, and mesothelioma s have been documented in association with very low lev els of community or household contact with asbestos. Mesothelioma rates are very low in the general population (age

adjusted incidence rate approximately 1 per 100,000) , and may have exceptionally lo ng latency

— perhaps as much as 40 years

— making excesses di fficult to detect in epidemiologic studies.

 The committee recommends that cancer of the ovary (C569) be listed as a WTC

- related condition. IARC has found sufficient evidence that asbestos exposure causes ovarian cancer. The incidence of
ovarian cancer is relatively low (age

- adjusted incidence rate approximately 6 per 100,000 women) and therefore difficult to detect in epidemiologic studies.

 The committee recommends that cancers of the urinary tract, including urinary bladder (C670

- 67 9 ), kidney and renal pelvis (C649, C659), ureter (C 669), and other urinary organs (C680

- C689) , be listed
as WTC

- related conditions. IARC found limited evidence that exposure to “arsenic and inorganic arsenic compounds” and “cadmium and cadmium compounds” causes kidney cancer, sufficient evidence that arsenic and inorganic arsenic compounds” cause cancer of the urinary bladder, and limited evidence that diesel engine exhaust and soot cause cancer of the urinary bladder. Transitional cell cancers of the renal pelvis, ureter and urinary bladder have been associated with a number of occupational and environmental exposures.

 The committee recommends that cancer of the eye and orbit (C690

- C6 99) be listed as a WTC

related condition

. Eye injuries were among the top three conditions tr eated formally in the first few days after 9/11 3 and, including informal, ad hoc eye irrigations on

- site, eye irritation by foreign bodies were by far the most co mmon acute treatments. Including cancer of the eye and orbit is5

consistent with including lip, skin and respiratory and digestive tract sites with direct dust and fume contact and irritation/inflammation related to WTC exposures.

 The committee recommends that thyroid cancer (C739) be listed as a WTC

- related condition. Thyroid cancer has not been associated with any of the agents known to be present at the WTC , and the primary evidence for an excess in risk comes from the Zeig

- Owens study 1

. I n that study, 17 thyroid cancers were observed and 6 expected based on national rates, yielding a statistically significant SIR of 3.07. The SIR was 5.21 and statistically significant compared with unexposed firefighters, and was 2.17 and significant after a two

- year lag was applied. The magnitude of the SIR for thyroid cancer was relatively large, although the significance of this finding is tempe red by the possibility that a 2

- year lag may not fully account for medical surveillance bias.

 The committee recommends that lymphoma, leukemia and myeloma ( see following link for ICDO

- 3 site and histology codes: http://seer.cancer.gov/siterecode/icdo3_d01272003/ ) be listed as WTC

r elated conditions

. All lymphatic and hematopoietic cancers (LHC’s) are combined in this document because of variation in how these cancers have been classified and grouped in epidemiologic studies , inaccurac y of death certificate diagnosis for these cancer s , and changes in clinical nomenclature over time. Various LHC’s have been associated in humans with exposure to benzene, 1,3

- butadiene, formaldehyde, polychlorophenols or their sodium salts (combined exposures), styrene and 2,3,7,8

- tetrachlorodibenzo

- para
- dioxin (Table 4 ). In addition, the Zeig

- Owens study found a statistically significant increase in non

- Hodgkin lymphoma which was only modestly attenuated when adjusted for surveillance bias. C ase – series reports have noted that a potential excess of multip le myeloma among WTC responders 4

. LHC’s are associated with a variety of carcinogenic exposures ; e levated rates of some LHC’s have been observed in atomic bomb

sur vivors as well as cancer patients treated with radiation and some forms of chemotherapy. The average latency for LHC’s after radiation or chemical exposure is generally shorter (< 10 years) than for solid tumors ( ≥ 20 years)

. Many leukemogens, including be nzene, radiation and chemotherapy agents are associated with bone marrow toxicity at high doses. Some LHC’s are associated with immunosuppression (such as AIDS

- related lymphomas) while others appear to be related to immune stimulation, including inflammati on 5

. It is increasingly recognized that many LHC’s have
pre
- clinical phases, and the STAC recommends that the pre
- malignant and myelodysplastic diseases be included as WTC

- related conditions as well.

 The committee recomm ends that childhood cancers (all cancers diagnosed in persons less than 20 years old) be listed as WTC

- related conditions. The unique vulnerability of children to synthetic6

chemicals commonly found in the environment has been documented in the landmark 199 3 US National Academy of Sciences report 6

. Children drink mo re water, breathe more air and eat more food per pound, and have higher exposures than adults 7 , 8

. In addi tion, childhood cancers are rare (total incidence of 15 per 100,000 children age 0

- 19) and excess risks are not likely to be detectable in the small number of children being followed in epidemiologic studies.

 The committee recommends that rare cancers be listed as WTC

- related conditions. There is no uniform definition of a rare cancer, and the committee recommends that definitions be based on
age
- specific incidence rates by gender, decade of age, site and histology. Site/histology
combinations to be consid ered as unique cancers should be determined a priori in consultation with appropriate experts.

 The committee recommends that breast cancer (C500

- 509) be added to the list of covered conditions. There is evidence of PCB exposures to WTC responders and su rvivors based on air samples 9 , window film samples 10 and one biomonitor ing study 11

. Studies have linked total and
congener
- specific PCB level s in serum and adipose tissue with breast cancer, although evidence has been conflicting 12

- 17

. PCBs and some other substances at the WTC site are endocrine disruptors

. Breast cancer risks are highly related to hormonal factors, including endogenous and exogenous estrogens, and could plausibly be affected by endocrine disruptors. A recent study found that PCBS enhanced the metastatic properties of breast cancer cells by activating rho

- associated kinase 18

. Shiftwork involving circadian rhythm disruption has been classifi ed by IARC as probably carcinogenic to humans, based in part on epidemiolog ic studies associating shiftwork with increased risks of breast cancer 19

. Both shiftwork and long shifts were common for workers involved in rescue, recovery, clean up, restoration and other activities at the WTC site. Final ly, the Committee recognizes that the main source of data used to identify sites of cancer that might be associated with WTC exposures is studies of industrial workers, which have often been limited to men because so few women worked in these occupations. Thus, the opportunity to find evidence for associations between occupational and environmental exposures and female breast cancer has been very limited. The Committee recognizes that additional epidemiologic studies will soon become available , and

recomme nds that as they do become available, their findings be reviewed and modifications made to the list as appropriate. The Committee also recommends that , in addition to treatment for the listed cancer sites, the WTC Health Program provides funding and guide lines for medical screening and early detection based7

on a review of evidence regarding the risks and benefits of the relevant screening and early detection modalities and appropriate counseling for individuals offered such screening. With respect to the use of the IARC data to identify potential cancer sites in humans, the committee wishes to emphasize that the body of evidence regarding carcinogenicity of substances present in WTC dusts and smoke is not limited to those considered by IARC to have suffici ent or limited evidence of carcinogenicity in humans. Many substances present in WTC dusts and smoke have been classified by IARC as known, probable or possible carcinogens based on animal studies and mechanistic data, and the committee believes that such evidence is highly predictive for human carcinogenicity. However, because there is limited concordance between specific cancer sites affected in humans and in animals, only those substances classified based on human data are informative regarding organ sit es of carcinogenicity in humans. In addition to the evidence considered by the committee to identify potential WTC

- related cancers, arguments in favor of listing cancer as a WTC

- related condition include the presence of multiple exposures and mixtures wit h the potential to act synergistically and to produce unexpected health effects, the major gaps in the data with respect to the range and levels of carcinogens, the potential for heterogeneous exposures and hot spots representing exceptionally high or uniq ue exposures both on the WTC site and in surrounding communities, the potential for bioaccumulation of some of the compounds, limitations of testing for carcinogenicity of many of the 287 agents and chemical groups cited in the first NIOSH Periodic Review, and the large volume of toxic materials present in the WTC
towers . Although acknowledging some lack of certainty in the evidence for targeting specific organs or organ site groupings as WTC

- related , the majority of the committee agreed that recommend ing t he specified cancer sites and site groupings was based on a sound scientific rationale and the best evidence available to date. We appreciate the opportunity to consider this important issue and would be happy to provide clarification or respond to any que stions you may have.

Sincerely,

Elizabeth M. Ward, PhD Chair, World Trade Center Scientific Advisory Committee8

Supporting documentation for the Committee’s r ecommendation

Table of Contents

1) Evidence regarding carcinogenic exposures pg. 10 a) Asbe stos pg. 1 2 b) Polycyclic aromatic hydrocarbons pg. 14 c) Polychlorinated biphenyls, dioxins, furans pg. 1 6 d) Particulates pg 1 7 e) Carcinogenic Metals pg. 19 f) Volatile organic compounds (VOCs) pg. 19 2) Mechanisms of carcinogenesis and role of i nflammation pg. 20 a) Overview of carcinogenesis pg. 20 b) Mechanistic data on chemical carcinogenesis pg. 21 c) Mechanisms of specific WTC human carcinogens pg. 2 1 d) WTC

- related r espir atory conditions and i nflammat ion pg. 23 3) Evidence regarding cancer from incidence studies pg. 2 4 4) Inclusion of rare cancers pg. 26 5) Inclusion of childhood cancers pg. 279

1. Evidence r egarding carcinogenic exposures The collapse of the World Trade Center produced a dense dust and smoke cloud containing gypsum from wal lboard, plastics, cement, fibrous glass, asbestos insulation, metals, and volatile and semi

volatile organic compounds and other products of high

- temperature combustion from burning jet fuel , heating oil, transformer oil and gasoline 20 , 21 . Individuals caught in the dust cloud on 9/11 and working on or near the site in the days immediately following the attack experi enced intense acute exposures to a mixture of substances whose concentration and composition was not measured and will never be fully known. However, it is known that the dust was highly alkaline, due to pulverized cement and other construction materials , and contained numerous particles, fibers and glass shards, resulting in acute eye, nose and throat irritation , leading rapidly to what came to be known as WTC cough. Smoke from fires that persisted into December 2011 contained polycyclic aromatic hydrocarb ons, metals, organic chemicals and many other known or potential carcinogen s

. Heavy equipment and trucks contributed diesel emissions, and there was repeated resuspension of sediment and dust during the subsequent 10

- month demolition and cleanup process. A lthough levels of airborne contaminants were not measured in the first four days, the high prevalence of acute and chronic respiratory conditions in rescue, recovery,

c lean

- up and restoration workers provides evidence for significant exposure levels and to xicity 22

. Although some of the dust and smoke was carried away into higher levels of the atmosphere, significant amounts settled in surrounding streets, residenc es and office buildings. Dusts entered buildings through broken windows, open windows, and air intakes, and highly respirable particles entered through closed windows. M any residents returned to homes that were highly contaminated and/or not adequately

rem ediated. Area residents and workers exposed to WTC dust have also been affected by chronic respiratory diseases, including newly diagnosed asthma and asthma exacerbation 23

. Members of the STAC and individuals providing public comments have noted that exposures resulting from collapse of the World Trade Center were unlike any other exposures in intensity and variety in history. We believe that to be the case, both because of the enormous forces that pulverized the buildings and their contents and the combustion products generated by the high

- temperature fires. Compounding the uniqueness of the exposures is the absence of any data on air contaminant levels or the co mposition of the dust and fumes in the first four days after the attack , and the presence of multiple and complex exposures . However, while acknowledging these unknown and unknowable factors, we believe that it is possible to make some judgments about the potential increased risks of developing some cancers based on the substances known to have been present. This information can be10

gleaned from a var iety of sources, including peer

- reviewed literature, government reports and unpublished reports from private laboratories and contractors. Based on these reports, t he committee believes that both responder populations and area residents and workers had potential for significant exposures to toxic and carcinogenic components of WTC dust and smoke. Factors that in fluence the intensity of exposures among individuals engaged in rescue, recovery, demolition, debris cleanup and/or other related services include the time and date of
arrival at the WTC site and other areas where WTC materials were transported or stored, total days and hours worked, specific jobs performed, breathing rates, work locations , particularly work in areas of smoldering fires, and availability and use of personal protective equipment and other controls

. Especially in the early period of rescue an d recovery, many individuals worked long shifts without adequate respiratory protection and in clothing saturated with dust from the debris, likely experiencing significant exposures through inhalation, ingestion, and skin absorption. Although these exposu res may be considered relatively brief compared to longer exposures typically associated with occupational cancer, many individuals had high

- intensity exposures, especially in the early weeks, and many continued to work in the area for weeks and months. Nu merous animal studies provide evidence that brief exposures to carcinogens can cause cancer. Evaluation of the Single

- Exposure Carcinogen Database containing 5576 studies involving 800 chemicals from 2000 articles showed that in 4271 of the studies, a sing le dose of an agent administered by multiple routes of exposure caused tumors to develop in many different animal models. In addition to PAHs, many of the tested chemicals are environmentally relevant and are on various pollutant lists, including the IARC and NTP lists. In support of the relevance of the single

- exposure carcinogen concept to human cancer, Calabrese and Blain 24 identified published occupational studies on benzene, beryllium, aromatic amines including benzidine, and arsenic in which exposures for less than a year were implicated as the causal factor in the development of cancer. In addition, studies of second or higher order tumors among cancer su rvivors have shown that both radiation therapy and some forms of chemotherapy increase risk for subsequent cancers, often with shorter latency periods than observed for lower

- dose, longer

- duration occupational and environmental
exposures 25

. Recent in vivo and in vitro studies using biomarkers of gene expression are consistent with potential increased cancer risks following relatively brief exposures to carcinogenic agents. The results of these studies indicate that the multistep process of chemical carcinogenesis can begin following exposures that range in duration from 1 to 90 days. In addition, some of the chemicals, dusts, fibers, metals and other materials with long half

- lives may be retained in the lung and other body compartments for long periods after an environmental exposure.11

Exposures among community residents and those working and attending school in the area also have the potential to be significant, although in many ways they may be even more difficu lt to categorize than those of responders. Some residents were not evacuated; s ome individuals returned within days of the disaster to grossly dust

- contaminated homes that they cleaned themselves; others returned to homes with less visible contamination th at were later found to contain high levels of asbestos and other toxic substances 26

. Many government offices are housed in buildings below Canal
Street , and many wor kers were required to return before any decontamination or cleaning took place and without personal protective equipment. Others worked, attended school or lived near sites where debris was transported or transferred in processes that continued to generate dusts. Still others volunteered in support activities near the site as well as residing in the community. Residential , office and school building exposures have the potential to be of longer duration than those among workers at the site if the buildings a nd occupied spaces were not properly remediated. Longer, lower

- level exposures may be a particular issue for individuals with preexisting asthma and allergies and those who are already sensitized to dust contaminants such as nickel and hexavalent chromium. Children in contaminated homes , daycare settings and schools have greater exposure potential than adults due to crawling on floors, hand

- to

- mouth activities and higher respiratory rates, and may also be more susceptible to mutagens and carcinogens due to growth and rapid cell turnover. In discussing the potential that exposures to WTC dust and smoke may cause cancer, the committee focused on classes of exposure known to be present in substantial quantities in WTC dust and smoke which also have substantial evidence regarding cancer in animals and humans. These include asbestos, polycyclic aromatic hydrocarbons (PAH’s), polychlorinated biphenyls, dioxins and furans, metals and volatile and semi volatile organic compounds (VOC’s). In addition, we considered s ome contaminants present in lower quantities due to potential toxicity and/or bio logical persist e nce ( polychlorinated biphenyls, dioxins and furans ).

a. Asbestos As presented by committee member Dr. John Dement, asbestos is designated as a known human
carcin ogen by IARC, with sufficient evidence for cancer of the larynx, lung, mesothelioma and ovary and limited evidence for cancer of the colorectum, pharynx and stomach. Bulk samples of outdoor dusts collected on September 16, 2001 on Cortland Street, Cherry A venue, and Market Street, outside the perimeter of the WTC site, had 0.8 to 3% asbestos by weight 27 . Air concentrations of dust were estimated to be in excess of 1 00,000 μg/m 3 21 , and persons exposed to the dust cloud may have12

experienced the equivalent of a lifetime of urban air particulate exposures 28 . The main source of asbestos was the chrysotile used to insulate the lower half of the first towe r. Chrysotile fibers in the WTC dust were predominantly shorter than 5 μm and/or less than 0.3 μm in diameter, and therefore not measured in the Phase Contrast Microscopy (PCM) method used by NIOSH and OSHA for determining compliance with OSHA Permissible Exposure Limits (PELS). Dr. Dement noted that fibers < 5 μm in length also predominate in occupational settings 29 and represent the predominant exposures to

wo rkers used for cancer risk assessments. Fibers < 5 μm in length represent 90% or more of the total airborne fiber exposures in South Carolina and North Carolina asbestos textile plants , where excess risks of lung cancer and mesothelioma have been well

- docu mented 30 , 31

. Selection of the PCM sampling method that did not count fibers < 5 u m in length was historic ally based on sampling reproducibility and feasibility, and not strong data demonstrating lack of toxicity of shorter fibers. Animal studies have suggested that longer fibers are more effective in producing lung cancer and mesothelioma than shorter

ones , b ut this has not been addressed extensively i n human studies which always involve mixed length fibers. Recent studies of asbestos textile workers in which size

- specific exposures to chrysotile were estimated by transmission electron microscopy found all tha t exposures to all fiber lengths were strongly predictive of lung cancer risk with a higher risk for longer and thinner fibers 29 , 32

. All forms of asbestos are carcinogenic, although it appears that amphibole asbestos has the highest potency for inducing mesothelioma. Amphibole asbestos does not appear to have been present in significant quantities at the WTC site. Numerous risk assessments have been done for asbestos based on data from occupational cohorts , and there has been no documented threshold below which cancer does not occur. Additionally, the exposure metric used for occupational risk assessments is cumulative
exposure , expressed as the product of exposure level by PCM and exposure duration (fiber

- years) , and short

- term exposures to high airborne concentrations have been associated with increased cancer risk. Inhaled asbestos fibers are retained in th e lung for periods of months to years and are able to migrate into the pleural and peritoneal cavity , where they induce pleural plaques and mesothelioma. The relative risk of lung cancer from exposure to asbestos and other lung carcinogens, such as tobacco smoke, is between additive and multiplicative. Case

- control studies of mesothelioma have documente d odds ratios in the range of 4

– 8 for asbestos exposures below 1 fiber years 33 , 34 . The risk assessment that OSHA used to set the PEL of 0.1 fibers > 5 μ m in length per cm 3 as an 8

- hour time

- weighted average exposure found that exposures to 0.1 f/cc over a working lifetime is associated with an excess risk of 3.4 cancers per 1,000 workers.13

b. Polycyclic Aromatic Hydrocarbons As presented by committee member Dr. Glenn Talaska, carcinogenic polycyclic aromatic hydrocarbons (PAHs) are among the earliest recogni zed human and animal carcinogens. Carcinogenic PAHs were largely responsible for the excess of scrotal cancer observed by Dr. Percival Pott among chimney sweeps, and were subsequently documented to cause cancer when painted on the skin or lavaged into the lungs of experimental animals. PAHs are produced by combustion of wood, coal and any other carbonaceous material. PAH are important causes of occupational lung cancer among tobacco smokers, coke oven workers, aluminum workers and other occupational groups. Because PAHs are formed from combustion, they always occur in occupational and environmental settings in combination as complex mixtures and it is therefore not possible to isolate the effect of a single compound in epidemiologic studies . The carcinogenic ity of specific PAHs has been evaluated by IARC based on evidence in animals and mechanistic considerations. Benzo(a)pyrene is listed by IARC in Group 1 (carcinogenic), Dibenz[a,h]anthracene is listed in Group 2A (probably carcinogenic) , and Benz[a]anthrac ene, Benzo[b]fluoranthene and Benzo[k]fluorenthene are listed in 2B (possibly carcinogenic). PAHs are absorbed by the body and metabolized to compounds that can bind to DNA. The major metabolites of PAHs excreted in urine are the monohydroxy PAHs, which ty pically have relative ly short biological half

- lives (4.4 to 35 hours ) 35 . Sources of PAH’s at the WTC included the burning of about 90,000 liters of jet fuel, 500,00 0 liters of transformer oil, 380,000 liters of fuel oil and approximately the same amount of gasoline plus any and all burning items. Heavy machinery and power tool brought to the site added to particulate and PAH exposures. Sampling data regarding PAH’s a re extremely limited; area samples were collected a t the fence line beginning 9/16/ 2001. I t was reported that PAH levels from the fires after 9/11 were among the highest ever reported from an outdoor sources 36

. Unfortunately, the samples were stationary area samples designed not to estimate exposures of worke rs on the pile, but the levels at or near ground level at the periphery to capture what might be leaving the site. It is documented that when area samples are not designed to capture the worst exposure case, they can underestimate personal worker
exposure by from 3

- to 40

- fold 37 , 38

. The vertical velocity of the smoke from the fires at the site would be th e major reas on that samples anywhere from 4

– 6 blocks from the pile itself would be lower than the personal exposures of the workers on the pile. As the authors state in their paper, “...workers engaged in the cleanup efforts could have been exposed to much h igher levels of PAHs than those in our samples and, thus, could bear higher cancer risks ” 36 Indeed, another set of samples taken 13 blocks from the pile were approximately 50% lower than the average of the 3 sites at the fence line. Pliel et al

. 36 also did not14

report whether there were any consistent differences in PAH levels between the 3 fence line sites , whic h would have occurred if there were spatial differences consistent with wind patterns or absolute distance from the pile. The analysis of PAH levels by Pliel et al. 36 in PM 2.5 was also retrospective and opportunistic. Analysis was limited completely to PAH remaining in the particulate phase captured on filte rs and not intended specifically for PAH analysis. Thus, any PAH in the vapor phase would not have been included in the analysis. Burstyn et al. (2002) 39 reported that the PAH in the vapor and particulate phases contributed equally to total PAH exposure in other workers. Pliel et al. used non

- linear regression to estimate the levels of PAH exposure on September 11, 2001 from the sam pling data tha t was collected beginning September 16, 2001. They estimate that maximal exposure would have been 35 ng/ m 3 36

. Butt et al. ( 2004 ) 10 measured the PAH levels in window films from buildings that varied in di stances and orientation from the ground zero pile. They reported that upwind sites greater than 2 km from the pile had levels of 6000 ng/ m 3

. This could be cons idered background. In contrast , those sites that were within 1km averaged 77,100 ng/m 3 , and those within 1 km and downwind from the site averaged 130,000 ng/m 3

. While these data cannot be used for exposure estimates they do give an indication of the variation due to proximity and whether or not an window was in the overall plume. Thus, it would appea r that the PAH exposure estimates taken from t he area samples probably underestimated the exposure of worker s on the pile. The magnitude of the underestimation is impossible to estimate , but indications are that it could be an order of magnitude or greate r. When done appropriately , biological monitoring can be a very useful in estimating exposure. Biomonitoring integrates exposure by all routes, including the use or misuse of personal protective equipment. Biomonitoring can also be used to reconstruct exp osures , provided the half

- life of the biomarker and the time since the last exposure are documented. The half

- life for the most wi dely used PAH biomarker , 1

- hydroxypyrene (1HP) , is effectively ~24 hours for persons without chronic exposure

40 , 41 . This means that 1HP largely represents the exposure of only the last 24 hours. Biological samples for PAH were also taken for exposure analysis 42

. Unfortunately these samples were o btained for 365 firefighters 22

– 24 days after 9/11/01. Assuming that the shape of the exposure curve estimated by Pliel et al. 36 are cor rect (however, as discussed above, the absolute values are likely underestimated for workers on the pile), then the 1HP levels measured are estimates of exposures that were much, much lower th an the peaks that occurred 9/11

– 9/14. Nonetheless, the 1HP level s remained significantly increased over what was seen in firefighters who were not at the WTC site. Since more tha n 99.99% of15

the 1HP resulting from exposures immediately after 9/11 would have been eliminated well before the samples were collected, the Ede lman data cannot be used to estimate exposure for that time. Rather they will reflect the ex posure during the previous 24

- hour period. The other shortcoming of the Edelman paper was that the r e was no indication of when the samples were taken relative to th e person’s last exposure. In addition, there is no indication of the distribution of the data within the
groups , and only the mean data are given without an idea of the vari ance. The important questions

— namely, were there some individuals with higher expos ure in the previous 24 hours a nd what tasks did they perform

— cannot be addressed either , since this information is not provided. There are also concerns that PAH may have been adsorbed unto particulates and form large masses in the lung from which the PAH would only be slowly absorbed into the body 43

. Unfortunately the biomonitoring data provided by Edel man et al. 42 cannot be used to determine if this possibility was in fact real , since only one sample was collected from each worker.

c. Polychlorinated biphenyls, dioxins, furans Polychlorinated biphenyls (PCBs) were present in the transformer oil in the electrical power substation that was located in the World Trade Center. In the area air sampling results reported by Lorber et al. 9
, a large numbe r of chemically different congeners, which contain different amounts of chlorine substituted at different places in the biphenyl rings , are treated as the same material

. These
samp les were taken to characterize outdoor inhalation exposures incurred by the “general population” defined as individuals living and working in neighborhoods surrounding GZ , and specifically did not address exposures that could have occurred to workers on th e site or in indoor environments. Among the hundreds of samples analyzed for PCBs , only one sample was above 100 ng/m 3
, and only three were greater than 50 ng/m 3 9

. Air levels around GZ were said to be reduced fairly quickly to “no rmal” ambient urban levels of 1

– 8 ng/m 3

. This might be expected since PCBs have an extremely low vapor pressure and dermal absorption of PCB’s from contaminated surfaces is thought to be a significant route of exposure. Once absorbed, PCBs have a fai rly long half

- life in the body , so bio logical monitoring should capture the
exposure. Edelman et al. 42 sa mpled for 31 PCB congeners 21 days after 9/11 and found that there was not a statistically significant difference between any of the mean values of firefighters on or who never entered the GZ site. On the other hand, Dalgren et al. 11 saw that certain PCB levels were markedly elevated in the sera of seven first responders compared to general population norms . For example, all

seven were above the median value found in the CDC NHANES study , three were above the 75 th percentile, two above the 90th and one above the 95 th percentile. For several measured congeners the 216

highest firefighters had levels above the NHANES detection limit, where 95% of the unexposed population was below it. The se data indicate that PCB levels in the sera of at least some first responders were elevated relative to the general population. D ioxin

- like compounds were present at elevated levels in the air immediately after 9/11/01. These compounds are formed when chl orinated plastics like PVC are burned under certain conditions of temperature, oxygen and pressure. The levels of dioxin and dioxin

- like compounds (furans and various congeners) were markedly elevated in initial area samples taken at the periphery of the W TC site (Ground Zero, GZ) 9

. (Please see the discussion of PAH for the limitations of these samples to estimate exposure for those at GZ itself.) At least 6 sample s taken in late September or early October yielded levels of total TCDD equivalents greater than 100 pg TEQ/m 3 , with the highest levels measured being 170 pg TEQ/m 3

. These were the highe st ambient levels ever recorded

9

. In comparison, typical urban ambient measurements or approximately 0.1 pgTEQ/m 3 and levels reported downwind from incinerators are on the order 1

- 5 pgTEQ/m 3

. This would indicate substantial
exposur e to dioxin

- like compounds. The USEPA did not find elevated levels of TCDD in house dusts. However, analyses of window films obtained from buildings at various distances from the WTC found that concentrations of 2,3, 7,8

- TCDD were 400 times higher i n a samp le from Church and Warren Street than samples taken at New York University and in Brooklyn 44

. Di oxins have relatively long half

- lives i n the human body; for TCDD half

- life is estimated to be 7
years (MMWR, 1988). Edelman et al. ( 2004 ) 42 measured 15 dioxin

- like compounds in t he sera of ~350 firefighters

. Only one congener was higher in the exposed firefighters compared to those who did not enter the site. The mean values were 27.8 ppt for all on site firefighters, 30.1 ppt for those present at the collapse, 26.2 ppt for those arriving after the collapse (day 1 and 2) and 3 0.6 ppt for those in Special Operations Command. Fire fighters not at the site had an average level of 19.2 ppt. There was no increase in TCDD levels compared to controls (please see PAH discussion for the limitations of the data presented in Edelman et al. , 2004). In contrast, the average levels reported in blood samples drawn approximately ten years after exposure for military personnel involved in spraying Agent Orange was 49 ppt and ranged to 313 ppt. This work reported that 20 ppt was the highest level generally seen in the general population. Again, no significant increase in TCDD levels were reported by Edelman, et al.
2004. 42 , 45

d. Particulates Particulates include non
- fibrous and fibrous inorganic particles

. T he non

- fibrous are silica, coal mine dust, and a variety of metallic and non

- metallic crustal silicates. S ilica (quartz) is an IARC Group 117

carcin ogen based on sufficient evidence for cancer of the lung in humans and also causes silicosis, a non

malignant lung disease characterized by scarring and inflammation. The fibrous particles include the commercial types of asbestos , which are all known carci nogens (chrysotile, amosite, crocidlite, anthophyllite). These are all hydrated magnesium silicates, and the main non

- asbestos fiber that is a known carcinogen is the fibrous zeolite erionite. Erionite is a fibrous aluminum silicate. Other fibers may
conta minate commercial products and be a cause of cancer , including tremolite and possibly other fibers in vermiculite. Man

- made vitreous fibers, rock wool, fibrous glass, glass shards, and other fiber

like fragments were also present in significant quantities. Man

- made vitreous fibers, refractory ceramic fibers and special

- purpose glass fibers are classified by IARC as Group 2B, possibly carcinogenic to humans. Glass wool, rock wool, and slag wool are classified as Group 3, not classifiable as to their carcinog enicity in humans 46

. The NTP classifies ceramic fiber s (respirable) and glass wool fibers (inhalable) as reasonably anticipated to be human carcinogens 47

. It is recognize d that some of the glass fibe rs present in WTC dust were subjected to tremendous heat and are degraded from their fibrous form

. In addition, many of the particles have been burned and some are coated with other materials.
C hanges resulting from high

- temperature fires have the potentia l to either exacerbate or reduce the toxicity of particles and fibers

.

Air pollution epidemiological s tudies have shown that PM less than 2.5 microns is associated with increased mortality for lung cancer in studies of the cohort formed by the American Cancer Society 48 and studied using time

- series in Metropolitan Statistical Areas with PM measurements over time, and corroborated by the Harvard six

- cities study 49 followed p rospectively. In addition, biomass indoor air pollution from poorly ventilated cooking stoves has been noted to increase lung cancer in

women 50

. Die sel exhaust has been implicated as a cause of lung cancer in large mortality studies of railroad workers 51 and recently in non

- metallic underground miners 52

. This latter cohort of more than 10,000 miners exposed to high diesel exhaust concentrations without confounding by radon had more than a 25% increase in lung ca nce r mortality. A subsequent case

– control study corroborated this increase and differentiated the risk from cigarette smoking 45

. A small body of evidence exis ts on lung particulate burden based on sputum, bronchoalveolar lavage and tissue analysis, primarily from symptomatic WTC

- responders. A b ronchoalveolar lavage stud y of a firefighter who developed eosinophilic pneumonia after worked on the pile for the firs t two weeks after 9/11 found 305 fibers per million alveolar macrophages, including chrysotile and amosite asbestos fibers , chromium, degraded glass fibers, fly ash and many silicates 53 , 54

. Sputum samples obtained from 39 WTC

- exposed FDNY18

firefighters ten months after 9/11 found a higher proportion of large and irregularly shaped particles and many more metallic eleme nts compared to firefighters from Tel Aviv 55

. Minerologic analyses of biopsy samples from lungs of seven symptomatic responders who were exposed to WTC dust on 9 /11 and 9/12 found variable amounts of sheets of aluminum and magnesium silicates, chrysotile asbestos, calcium phosphate and calcium sulfate, small shards of glass and carbon nanotubes of various sizes and lengths 56

. A study of twelve WTC

- exposed patients local workers, residents and clean up workers) found
opaque an d bi refring e nt particles within macrophages, with particles containing silica, aluminum silicates, tit anium dioxide, talc and metals undergoing lung biopsy 57

.

e. Carcinogenic metals As noted in Table 1 and 2 , five metals measured in ETC dust and air samp les are listed as known human carcinogens by IARC; all increase risk for lung cancer with other cancer sites of sufficient or limited evidence in humans varying by metal. As with other WTC exposures, varying exposure levels have been reported and monitorin g was limited 9 , 58

. In general, however, the concentration of carcinogenic metals in settled dust and smoke sampl es was low compared to concentrations of non

carcinogenic metallic elements. For example, in dust samples collected at Cortland, Cherry and Market Street, concentrations of titanium and zinc were over 40 times the concentration of nickel, the most

common of the carcinogenic metals measured 27

. Cahill and colleagues developed the “ incinerator hypothesis ” to explain the presence several carcinogenic metals in aerosol plumes in October 2011, apparently liberated from burning d ebris at temperatures at which they would not normally volatilize 59

. Groups at risk for metal exposures include workers at the WTC site (plume lofting was thought to protect wider areas of NYC ) and responders and survivors with short

- term exposure to the initial dust cl oud and those with longer

- term exposure to dusts in homes, schools and offices or during cleanup 60

. Some metals, such as cadmium, bioaccumulate in the body, resulting in persistent exposure from endogenous sources. Further factors raising concern for metals include the potentially large load deposited in the lungs of those in the initial WTC collapse , with uncertain impact on half

- life and
interaction wi th high dust pH.

f. Volatile organic compounds (VOCs) As noted in Table 1, three VOCs, benzene, 1,3 butadiene and formaldehyde, are listed as known human carcinogens by IARC; all increase risk for lymphatic and hematopoietic cancer . Formaldehyde also inc reases risk for nasopharyngeal cancer with limited evidence for nasal cavity and paranasal sinus19

cancer. Hematopoetic cancers, such as leukemia, have the shortest latency of the chemically

- related

cancers , so it is biologically plausible that leukemias dia gnosed to date in exposed WTC populations are related to 9/11. Other VOCs, such as tetrachloroethylene and trichloroethylene, are considered group 2A probable human carcinogens that impact the hematopoetic system. Benzene, 1,3 butadiene and formaldehyde ar e common exposures present in combustion products. Groups with potential for exposure to these VOCs include workers on the pile and those exposed to diesel exhaust. VOCs are not persistent in environment and do not accumulate in the body. As with other WTC exposures, varying exposure levels have been reported and monitoring was limited 9 , 27 , 61

. B enzene and 1,3

- butadiene were among the 11 VOCs monitored in and near GZ to determine if the area was safe for entry by rescue workers and firefighters 9 . These samples were mainly
4

- min ute samples , with a few 24

- hour samples. Of the VOCs monitored, benzene levels were noted to be measureable the greatest distance from GZ , with levels approach ing the ATSDR Intermediate (>14

– 364 days) MR L , although for a duration likely less than 45 days 9 . Descriptions of air in lower Manhattan and diesel exhaust 62 suggest that more frequent air monitoring would have indicated higher levels.

2. Mechanisms of carcinogenesis and role of inflammation

a. Overview of Carcinogenesis As presented by Committee member Dr. Eliz abeth Ward and elaborated on by Dr. Julia Quint , carcinogenesis is characterized by four stages: initiation, promotion, malignant transformation, and tumor progression. Initiation occurs when a carcinogen interacts with DNA, most often by forming a DNA add uct (a specific type of chemical bond) between the chemical carcinogen or one of its functional groups and a nucleotide in DNA, or by producing a strand break. If the cell divides before the damage is repaired, an alteration can become permanently fixed as a heritable error that will be passed on to daughter cells. Such heritable changes in DNA structure are called mutations. Many mutations have no apparent effect on gene function. However, when mutations occur in critical areas of genes that regulate cell growth, cell death, or DNA repair, they may predispose clonal expansion and accumulation of further genetic damage. Promoters are substances or processes that contribute to clonal expansion by stimulating initiated cells to replicate, forming benign tumors or hyperplastic lesions. Promotion is thought to be completely reversible. The process of promotion does not cause heritable alterations or mutations. It stimulates cell turnover, so that mutated cells can exploit their selective growth advantage and prol iferate, increasing the probability that a cell will acquire additional mutations and become malignant. Unlike promotion, the end result of malignant transformation is irreversible. Tumor20

progression involves the further steps of local invasion and/or meta stasis.

b. Mechanistic Data on Chemical Carcinogenesis and Current Uses of the Data Advances in the scientific understanding of cancer biology and the use of bioanalytical approaches (transcriptomics, proteomics, metabolomics, and toxicogenomics) have si gnificantly improved research on the mechanisms of chemical carcinogenesis. In addition to using established short

- term tests to determine whether chemicals damage DNA or cause genotoxic effects, scientists are now determining the effects of chemicals on e pigenetic mechanisms such as DNA methylation, apoptotic response, and cell signaling pathways. This is an important advancement because altered DNA methylation in key regulatory genes may be an early and significant event in the development of human cancer 63 , 64

. Cancer mechanistic data and information are currently used to predict carcinogenicity, to i nform the hazard identification process of cancer risk assessments, and to identify and classify agents that

cause cancer. Gene expression biomarkers can distinguish between carcinogens and non

- carcinogens in acute and subchronic in vivo and in vitro studi es, and can predict carcinogenicity with high degrees of specificity and sensitivity 65

- 69 . Tests based on toxicogenomic and classification methods eventually may replace the two

- year rodent cancer bioassays that currently are used to identify chemical carcinogens.
In its Guidelines for Carcinogen Risk Assessment 70 (US EPA, 2005), the US EPA emphasizes the use of mechanistic data in evaluating the modes of actions of chemicals. IARC relies on mechanistic and other relevant data, in addition to epidemiological studies and cancer bioassays, in a ssessing carcinogenicity. An agent is identified as carcinogenic to humans if there is sufficient evidence in animal bioassays and “strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity” 71 . The NTP, US EPA, and Germany have adopted IARC’s approach of using information on mechanisms of carcinogenicity 47 , 70

. Information obtained from mechanistic studies also may be used to classify cancer and predict its clinical course 69 , 72 and to identify new cancer therapies 72 ).

c. Mechanisms of Specific WTC Human Carcinogens and the Role of Inflammation Table 5 shows established mechanistic events related to causing human cancer for seven WTC human carcinogens 73

. The data support the view that chemicals agents act through multiple mechanisms or modes of action to induce cancer. Based on the strength of existing evidence, arsenic, chromium VI compounds, nickel compounds and asbestos induce cancer through both genotoxic and epigenetic modes of action. Beryllium acts through genotoxic modes of action, and cadmium and silica act through epigenetic modes of action. Chromium VI compounds, nickel compounds, beryllium, and21

asbestos can damage DNA through direct interactions, whereas arsenic increases oxidative DNA damage and does not interact directly with DNA. Inflammation is an established mechanism of asbestos and silica

- induced cancer in humans (Table 5). Based on several lines of evidence, inflammat ion also is postulated as a mechanism for human cancers caused by exposures to arsenic, nickel compounds, chromium VI, and beryllium (IARC, 2011). Inflammation can accelerate multiple stages of carcinogenesis and is thought to be an important factor in the development of cancer. It is a normal physiologic process in response to tissue damage resulting from chemical irritation and/or wounding. Inflammation usually is a self

- limited process that results in repair of damaged tissue. However, when inflammatory processes become chronic they may lead to persistent tissue damage that can predispose to cancer development. Critical evidence for the role of inflammation in carcinogenesis comes from clinical conditions that involve both inflammation and increased cance r risk. Examples include the inflammatory diseases, ulcerative colitis and Crohn’s disease, and predisposition to cancer of the large bowel; and chemical injury caused by chronic reflux of gastric acid and bile into the distal esophagus, and development of Barrett’s esophagus and esophageal adenocarcinoma 74 , 75

. Extensive experimental data on several WTC human carcin ogenic agents also provide evidence for the role of inflammation in carcinogenesis. Studies in animals show that asbestos fibers induce macrophage activation and persistent inflammation that contribute to tissue injury and cell proliferation. In a similar manner, rats exposed to crystalline silica develop a severe, prolonged inflammatory response that is characterized by elevated neutrophils, proliferation of epithelial cells, and lung tumors. Consistent with the effects of silica in rodents, a recent stud y showed significant, dose

- related secretion of cytokines and alterations in gene expression by human lung epithelial cells exposed for 24 hours to crystalline silica, but not to amorphous silica 76

. Arsenic

- induced increases in inflammation have been reported in numerous studies 77 . The inflammatory process involves arsenic activation of the transcription factor, NF

- kB 78

. In mice, low levels of arsenic promote progressive inflammatory angiogenesis, which provides a blood supply to tumors 77

. The NF

- kB inflammatory signaling pathway is activated in infant s born to mothers exposed to high levels of arsenic in drinking water 79

. A single exposure to particulate chromium VI results in inflammation of lung tissue in mic e that persists for up to 21 days. Repetitive exposure induces chronic lung injury and an inflammatory microenvironment that is consistent with the promotion of chromium VI

- induced lung

cancer 80

. Evidence that inflammation may contribute to nickel

- induced carcinogenesis is based on studies which show that nickel compounds cause significant increases in oxidative DNA damage with22

concomitant inflammation in the lung s of rats 81 . In a review of the available studies on beryllium

induced cancer, IARC concluded that “the inflammatory processes associated with the development of acute or chronic beryllium disease could plausibly contribute to the development of lung cancer by elevating the rate of cell turnover, by enhancing oxidative stress, and by altering several signaling pathways involved in cell replication” 73

.

d. WTC

- Related Respiratory Conditions and WTC Dust

— Evidence o f Inflammatory Processes A number of studies have documented the role of inflammatory processes in WTC

- related respiratory conditions. A bronchoalveolar lavage (BAL) study recovered significant quantities of fly ash, degraded fibrous glass, and asbestos fi bers along with evidence for a significant inflammatory response (70% eosinophils and increased levels of interleukin

- 5) in one FDNY f irefighter hospitalized with acute eosinophilic pneumonitis several weeks after WTC exposure 53

. Fireman et al. 55 , studied induced sputum samples obtained 10 months after the attack from 39 hi ghly exposed firefighters and found evidence for higher percentages of eosinophils and neutrophils (compared to controls) that increased with exposure intensity. A study conducted in a cohort of 801 never

- smokers with normal pre

- 9/11 FEV(1) found that
elev ated serum granulocyte macrophage stimulating factor( GM

- CSF) and macrophage

- derived chemokine (MDC) factor soon after WTC exposure were associated with increased risk of airflow obstruction in subsequent years. Surgical lung biopsies of twelve symptomatic WTC

- exposed local workers, residents, and cleanup workers enrolled in a treatment program found interstitial fibrosis, emphysematous change, and small airway abnormalities were seen. All cases had opaque and birefringent particles within macrophages, and examined particles contained silica, aluminum silicates, titanium dioxide, talc, and metals 59

. Elevated prevalence of sarcoid

- like granulomatous disease has also been observed among firefighters and other first responders 82

. Granulomat ous diseases arise from inflammatory processes including infection (tuberculosis) and beryllium exposure (chronic beryllium disease) 82

. Studies of the effects o f WTC dust particles on mice and on cultured human cells provide mechanistic evidence for the role of inflammatory processes in WTC

- related respiratory conditions. Gavett et al. found significant neutrophilic inflammation in the lungs of mice and an increa se in airway hyper

- responsiveness to methacholine challenge following exposure to a single oropharyngeal aspiration of fine WTC dust (mass

- median aerodynamic diameter of less than 2.5 μm or PM 2.5 ) 83

. Exposure of human primary alveolar marcrophages and type II epithelial cells, key lung cell populations, to WTC dust particles (WTC PM 2.5 ) caused time

- and dose

- related increases in the formation/release of23

pro
- inflam matory cytokines/chemokines that contribute to inflammation and airway remodeling
processes 84

. A recent study of WTC PM 2.5 exposure in lung epithelial cells demons trated that activation of mitogen

- activated protein kinase signaling pathway(s) likely played an important role in the dose

dependent increase of cytokine formation by the cells 85

. The authors postulate that WTC

- induced cytokine induction at low doses (0

- 200 μg/mL) and short time intervals (5 hr) in their study compared to the Payne et al. study (500

– 2000 μg/mL and 24 hr) 84 may help to explain why the incidence of asthma and other inflammation

- associated diseases were increased both in First Responders as well as among

m etropolitan area residents 20

– 30 miles away from Ground Z ero. Many exposures that cause cancer in the upper and lower respiratory tracts also cause non

malignant respiratory diseases. Examples include tobacco smoking, silica, asbestos, beryllium, particulate air pollution, and indoor exposures to the burning of biomass fuels

.

3. Evidence regarding cancer from completed incidence studies One study has been published regarding cancer outcomes among 9,853 men who were employed as firefighters as of January 1, 1996, and were or would have been less than 60 years o f age on 9/11/2001. 1 Of these, 8927 were WTC

- exposed. Cancers (excluding basal cell skin cancers) diagnosed between 1996 and 2008 were identified from five st ate cancer registries and from self

- reports on questionnaires administered during routine mandatory FDNY wellness evaluations performed every 12

– 18 months and subsequently verified by review of medical records. Risks of cancer were compared by calculating expected numbers of cancers during non

- exposed
person
- years (never

- exposed firefighters and period before 9/11 for exposed firefighters) and post

exposure person years, based on sex, age, race, and ethnicity

- specific cancer rates in the SEER

- 13 registries

. WTC

- exposed and non

- exposed SIR’s were calculated for the exposed and non

- exposed groups based on the ratios of observed and expected cancers in the general population each group. In addition, because firefighters constitute an unusually fit and healthy population who might be expected to have lower age

- adjusted cancer rates than the general population, SIR Ratios were calculated to assess differences in cancer rates between the two groups. Among a number of secondary analyses reported, the one considered the most relevant was an adjustment for early diagnosis (surveillance bias) through lagging the diagnosis dates for two years for all cancers potentially identified by WTC

- related medical screening in the FDNY medical surveillance program. Strengths of t he study included probably near

- complete case

- finding, reliable (albeit crude) exposure information, lack of selection bias, and inclusion of a control population with equivalent non

-24

WTC environmental and occupational exposures. Limitations include lack of representativeness for women, children, and elderly persons ; insufficient power to detect differences in most specific cancer types ; insufficient exposure data and insufficient variability in exposure to evaluate for a dose

- response effect ; and short foll ow
- up time relative to cancer latency. A total of 263 cancers were documented in 61,884 person

- years after WTC exposure, where 2 38 would have been expected from SEER

- 13 data, yielding a Standardized incidence ratio (SIR) of 1.10, with 95% confidence inter val spanning 0.98 to 1.25

— just missing statistical significance. For the 60,761 unexposed person

- years, however, the SIR estimate was 0.84 (0.71 to 0.99), indicating that, absent WTC exposure, firefighters have a lower than predicted cancer incidence (an e xample of the healthy worker effect). Comparing exposed to unexposed, the estimated SIR ratio was 1.32, with confidence intervals 1.07 to 1.62, demonstrating that WTC exposure increased risk of cancer approximately 32% over that expected in this worker pop ulation. After introducing an artificial 2

- year lag time in cancer diagnosis for thyroid, lung, and prostate cancers and for lymphoma (to “correct” for possible surveillance bias), the total number of diagnosed cancers in the exposed population would have been 242 and the estimated SIR ratio would have been 1.21, with confidence interval spanning 0.98 to 1.49 , again just missing statistical significance, but still far more likely than not reflecting a small excess of cancers among exposed firefighters. Arg uing against a more severe surveillance bias is that cancer staging did not demonstrate an earlier stage of diagnosis in the exposed as compared to the unexposed. For each individual type of cancer, too few cases were expected to have statistical power to detect moderate increases (or decreases) in cancer risk

. Howe ver, for thyroid cancer, melanoma, and

non
- Hodgkin Lymphoma, SIR s were substantially higher than 1.0 and approached statistical significance. Regarding prostate cancer, consistent with prior stud ies 86 , even the unexposed firefighters had slightly and statistically significantly higher incidence than predicted, with SIR 1.35. The WTC

- exposed FDNY group did not show an increased risk over the unexposed, with estimated SIR ratio 0.90 (after correction for possible surveillance bias). Therefore, despite the statistically significant SIR for prostate cancer in
WTC

- exposed firefighters compared to the general population, the overall results do not support an increased risk of prostate cancer associated with WTC exposures. Data from th e Zeig

- Owens study are presented in Table 4 for cancer sites with some evidence of increased risk

. Some of the cancer sites with excess risk in this study have been observed in prior studies of firefighters 86

. Additional post

- WTC cancer incidence results are expected to come from the non

- FDNY WTC Responder Consortium, the WTC registry cohorts , and the FDNY EMS cohort in the near future. The STAC has not25

had acce ss to those studies and therefore has not based current recommendations on them . Given the paucity of epidemiological studies to date, additional studies can be expected to inform the body of knowledge on the issue of WTC and cancer risk, though the limita tions of surveillance bias, sample size, selection bias, limited follow

- up and others are likely to persist.

4. Inclusion of rare cancers Excesses in rare cancers are difficult to detect in epidemiologic studies

. Even large studies may have very low numbe rs of expected cases of rare cancers , and thus very low statistical power to detect any but very large effects. In addition, most cancer studies analyze data by organ site, and not by site and histology. This can result in inability to detect rare site and histology combinations , such as angiosarcoma of the liver, associated with vinyl chloride monomer exposure, 87 and small cell carcinoma of the lung, associated wit h bis chloromethyl ether 88

. Cancers can also be defined as rare based on the patient’s gender (male breast cancer), age (prostate cancer in men under 40) or race (melanoma in African Americans). Since customary study methods are unlikely to identify increased risks for rare cancers among WTC

- exp osed populations unless they occur in sizable clusters

. Nonetheless, given the sizable number of carcinogens (and related cancer sites) present in WTC smoke and dust, it is reasonable

to consider the possibility that an increased risk of specific rare canc ers may occur or that the incidence of common cancers would be increase d at younger ages in WTC

- exposed populations. One approach that has been used is to consider rare cancers as cancers with age

- adjusted incidence rates less than 15 per 100,000, which wo uld result in defining 25% of all adult cancers in the US as rare 89 . Additional definitions

— 10 cases per million per year , or 1 case per million per year

— have also been examined 89

. For the purposes of defin ing rare cancers for the WTC Health Program, one approach would be construct a matrix of on age
- specific incidence rates by gender, decade of age, site and histology and to consider as rare any cancer with an incidence rate of < 5 or <10 per 100,000 in the appropriate gender age stratum for the site/histology combination. If this approach is adopted, s ite/histology combinations to be considered as unique cancers should be determined a priori in consultation with appropriate experts. However, it is clear tha t there are many reasonable approaches that could be used to define rare cancers and the STAC is not endorsing a specific approach at this time.

5. Inclusion of childhood cancers The unique vulnerability of children to synthetic chemicals commonly found in the environment has been documented in the landmark 1993 US National Academy of Sciences report. 6 Children drink26

more water, breathe more air and eat more food per pound, and have higher exposures than adults. 7 , 8 Their developing organ systems are also more vulnerable to many chemicals, and are less well able to detoxify or eliminate them

. 90 , 91 Together, these aspects of early life development increase the likelihood of lifelong organ system impairment following exposure to environmental chemicals. 92 Children also have more years of life in which chronic conditions can occur as a result of early life exposures. 93 Epidemiologic studies have associated exposure to benzene 94 , 95 , certain pesticides 96 , 97 , polychlorinated biphenyls 98 , 99 , and 1,3

- butadiene with increases in childhood malignancies. Children who attended schools and lived near the World Trade Center site experienced exposures in the range of responder p opulations 87

. Given the baseline relative infrequency in which cancer occurs in children, and the limited statistical power of even a study of all 14,000 children who lived south of 14 th Street on September 11, 2001, no negative study will eliminate the possibility of causation. Indeed, this is an area of need for research, yet such research should not preclude a measure of caution taken in including coverage for a ll cancers incident before age 21 insofar as a health care provider confirms substantial likelihood of association with World Trade Center exposures.2728



# I. Summary of Cancer Classifications for COPC and Select Other Agents

IARC Group 1

— Carcinogenic to H umans This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent may be placed in this category when evidence of carcinogenicity in humans is less than sufficient but there is sufficient evidence of carci nogenicity in experimental animals and strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity.

Agent Category

IARC NTP

Arsenic 1 A
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Arsenic.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol84/mono84

- 6E.pdf

Asbestos 1 A
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Asbestos.pdf
IARC hyperlink: http: //monographs.iarc.fr/ENG/Monographs/suppl7/Suppl7

- 20.pdf

Benzene 1 A
NTP hyperlink: http://monographs.iarc.fr/ENG/Monographs/suppl7/Suppl7

- 24.pdf
IARC hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Benzene.pdf
Benzo[a]pyrene (PAHs) 1 B

NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/PolycyclicAromaticHydrocarbons.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol92/mono92

- 10.pdf
Beryllium 1 A
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Beryllium.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol58/mono58

- 6.pdf29

Agent Category

IARC NTP
1,3

- Butadiene 1 A
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Butadiene.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol97/mono97.pdf

Cadmium and compounds 1 A

NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Cadmium.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol58/mono58

- 7E.pdf

Chromium VI 1 A

NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/ChromiumHexavalentCompounds.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol49/mono49

- 6.pdf
Formaldehyde 1 A
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/F ormaldehyde.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol88/mono88

- 6.pdf
Nickel compounds 1 A
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Nickel.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol49/mono49

- 7.pdf

Quartz 1 A
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Silica.pdf
IARC hyperlink: http://mo nographs.iarc.fr/ENG/Monographs/vol68/mono68

- 6.pdf

Soot 1 1 B
NTP hyperlink http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Soots.pdf
IARC hyperlink http://monographs.iarc.fr/ENG/Monographs/vol35/volume35.pdf

Sulfuric Acid 1 A

1 As found in occupational exposure of chimney sweeps.30

Agent Category

IARC NTP
NTP hyperlink: http://ntp.nieh s.nih.gov/ntp/roc/twelfth/profiles/StrongInorganicAcidMists.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol54/mono54

- 6.pdf
Vinyl chloride 1 A
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/VinylHalides.pdf
IARC hyperlink: http://monograp hs.iarc.fr/ENG/Monographs/vol97/mono97

- 8.pdf31



### IARC Group 2A
— Probably Carcinogenic to Humans This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some c ases, an agent may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans. An agent may be assigned to this category if it clearly belongs, based on mechanistic considerations, to a class of agents for which one of more members have been classified in Group 1 or in Group 2A.

Agent Category

IARC NTP 2

Benzyl Chloride 2A NL

NTP hyperlink: Not applicable
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol71/mono71

- 19.pdf

Biomass fuel
(primarily wood, indoor emissions from household combustion) 2A NL

NTP hyperlink Not applicable
IARC hyperlink http://monographs.iarc.fr/ENG/Monographs/vol95/mono95

- 6A.pdf
Dibenz[a,h]anthracene 2A B

NTP hyperlink: http://ntp.niehs. nih.gov/ntp/roc/twelfth/profiles/PolycyclicAromaticHydrocarbons.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol92/mono92

- 10.pdf
Engine Exhaust, diesel 2A B

N TP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/DieselExhaustParticulates.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol46/volume46.pdf

2 NL = not listed32

Agent Category

IARC NTP 2

Ethylene Dibromide 2A B

NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/pro files/Dibromoethane.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol71/mono71

- 28.pdf
Lead (inorganic) 2A B

NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Lead.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol87/index.php

Nitrate io n (ingested) 2A NL

NTP hyperlink: Not applicable
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol94/mono94

- 6F.pdf
Polychlorinated Biphenyls 2A B

NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/PolychlorinatedBiphenyls.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/suppl7/suppl7.pdf
Tetrachloroethylene 2A B

NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Tetrac hloroethylene.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol63/volume63.pdf
Trichloroethylene 2A B

NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Trichloroethylene.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol63/ mono63

- 6.pdf33



### IARC Group 2B
— Possibly Carcinogenic to Humans This category is used for agents for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in experimental animals. In some instances, an agent for which there is inadequate evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals , together with supporting evidence from mechanistic and other relevant data, may be placed in this group. An agent may be classified in this category solely on the basis of strong evidence from mechanistic and other relevant data.

Agent Category

IARC NTP 3

Acrylonitrile 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Acrylonitrile.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol71/mono71

- 7.pdf
Antimony trioxide 2B NL
NTP hyperlink: Not applicable
IARC hyperlink: http://monograp hs.iarc.fr/ENG/Monographs/vol47/volume47.pdf

Benzene Hexachloride
(syn: lindane) 2B B

NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Lindane.pdf
IARC hype rlink: http://monographs.iarc.fr/ENG/Monographs/suppl7/Suppl7

- 88.pdf
Benz[a]anthracene 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/PolycyclicAromaticHydrocarbons.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol 92/mono92

- 10.pdf
Benzo[b]fluoranthene 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/PolycyclicAromaticHydrocarbons.pdf

3 NL = not listed34 Agent Category

IARC NTP 3

IARC hy perlink: http://monographs.iarc.fr/ENG/Monographs/vol92/mono92

- 10.pdf
Benzo[k]fluoranthene 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/PolycyclicAromaticHydrocarbons.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/v ol92/mono92

- 10.pdf

Bromodichloromethane 2B B

NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Bromodichloromethane.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol71/mono71

- 73.pdf

Carbon tetrachloride 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/CarbonTetrachloride.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol71/volume71.pdf

Cobalt sulfate and so luble cobalt 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/CobaltSulfate.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol86/mono86

- 6E.pdf

Chlordane 2B NL
NTP hyperlink: Not applicable
IARC hyperlink: http://monographs.iarc.fr/E NG/Monographs/vol79/mono79

- 17.pdf

4

- Chloroaniline 2B NL
NTP hyperlink: Not applicable
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol57/mono57

- 21.pdf

Chloroform 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Chloroform.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol73/mono73

- 10.pdf
Chrysene 2B NL35 Agent Category

IARC NTP 3

NTP hyperlink: Not applicable
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol92/ mono92

- 10.pdf

DDT 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Dichlorodiphenyltrichloroethane.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol53/mono53

- 9.pdf
1,4

- Dichlorobenzene 2B B
NTP hyperlink: h ttp://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Dichlorobenzene.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol73/mono73

- 13.pdf
3,3'

- Dichlorobenzidine 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Dichlorobenzidine.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol99/mono99

- 10.pdf
p,p'

- Dichlorodiphenyl

- dichloroethane (TDE) 2B NL

NTP hyperlink: Not applicable
IARC hyperlink: http://m onographs.iarc.fr/ENG/Monographs/vol53/mono53

- 9.pdf
p,p'

- Dichlorodiphenyl

- dichloroethylene (DDE) 2B NL

NTP hyperlink:
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/ vol53/mono53

- 9.pdf
1,2

- Dichloroethane
(syn: Ethylene dichloride) 2B B

NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Dichloroethane.pdf
IARC hyperl ink: http://monographs.iarc.fr/ENG/Monographs/vol71/mono71

- 21.pdf
2,4

- Dinitrotoluene 2B NL
NTP hyperlink: Not applicable36 Agent Category

IARC NTP 3

IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol65/mono65

- 9.pdf
2,6

- Dinitrotoluene 2B NL
NTP hyperlink: Not applicable
IARC hyperlink: http:// monographs.iarc.fr/ENG/Monographs/vol65/volume65.pdf

1,4

- Dioxane 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Dioxane.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol71/mono71

- 25.pdf
Ethylbenzene 2B NL
NTP hyperlink: Not applicable
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol77/mono77

- 10.pdf
Heptachlor 2B NL
NTP hyperlink: Not applicable
IARC hyperlink: http://monographs.iarc.fr/ENG/Mon ographs/vol79/mono79

- 17.pdf

Hexachlorobenzene 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Hexachlorobenzene.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol79/mono79

- 18.pdf

Hexachloroethane 2B B
NTP hyperlink: h ttp://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Hexachloroethane.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol73/mono73

- 15.pdf
Indeno[1,2,3

- cd]pyrene 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/PolycyclicAromaticHydrocarbons.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol32/volume32.pdf
Methylene chloride 2B B37 Agent Category

IARC NTP 3
(syn: dichloromethane)
NTP hyperlink: http:/ /ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Dichloromethane.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol32/volume32.pdf

Mirex 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Mirex.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monogra phs/vol20/volume20.pdf
Naphthalene 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Naphthalene.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol82/mono82

- 8.pdf

Nickel metallic 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twel fth/profiles/Nickel.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol49/mono49

- 7.pdf

Nitrobenzene 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Nitrobenzene.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol65/mono65

- 1 1.pdf

N

- Nitroso

- Di

- n - propylamine 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Nitrosamines.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol17/volume17.pdf
Pentachlorophenol 2B NL
NTP hyperlink: Not applicable
IARC hyperlink: ht tp://monographs.iarc.fr/ENG/Monographs/vol71/mono71

- 34.pdf
Styrene 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Styrene.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol82/mono82

- 9.pdf38 Agent Category

IARC NTP 3

Titanium Dioxide 2B NL
NTP hyperlink: Not applicable
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol93/mono93

- 7F.pdf
Toxaphene 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Toxaphene.p df
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol79/mono79

- 19.pdf
2,4

- Toluenediisocyanate 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/TolueneDiisocyanates.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol71/ mono71

- 37.pdf
2,6

- toluene diisocyanate 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/TolueneDiisocyanates.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol71/mono71

- 37.pdf
2,4,6

- Trichlorophenol 2B B
NTP hyperlink: http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/Trichlorophenol.pdf
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol71/mono71

- 34.pdf

Vanadium Pentoxide 2B NL
NTP hyperlink: Not applicable
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol86/mono86

- 10.pdf
Vinyl acetate 2B NL
NTP hyperlink:
IARC hyperlink: http://monographs.iarc.fr/ENG/Monographs/vol63/mono63

- 19.pdf39



### Table 2 . Selected agents that IARC has classified as carcinogenic to humans and related cancer sites with sufficient or limited evidence in humans 100



### .

Carcinogenic agent Cancer sites with sufficient evidence in humans Cancer sites with

limited evidence in humans Acid mists, strong inorganic (Sulfuric acid) Larynx Lung Arsenic and inorganic arsenic compounds Lung Skin Urinary bladder Kidney Liver Prostate Asbestos (all forms) Larynx Lung Mesothelioma Ovary Colorectum Pharynx Stomach
Benzene Leukemia (acute nonlymphocytic) Leukem ia (acute lymphocytic, chronic lymphocytic, multiple myeloma, non

Hodgkin lymphoma) Beryllium and beryllium compounds Lung 1,3

- Butadiene Hematolymphatic organs Cadmium and cadmium compounds Lung Kidney Prostate Chromium(VI) compounds Lung Nasal cav ity and paranasal sinus Formaldehyde Leukemia Nasopharynx Nasal cavity and paranasal sinus Nickel compounds Lung Nasal cavity and paranasal sinus Silica dust, crystalline (in the form of quartz or crystobalite) Lung
Soot Lung Skin Urinary bladder

2 ,3,7,8

- Tetrachlorodibenzo

- para - dioxin All cancers combined Lung Non

- Hodgkin lymphoma Soft

- tissue sarcoma Vinyl Chloride Liver (angiosarcoma, hepatocellular carcinoma)40



### Table 2. Agents that IARC has classified as probably carcinogenic or possibly carcino genic to hu mans and cancer sites with limited evidence 100

Suspected carcinogenic agent Cancer sites with limited evidence in humans Engine exhaust, diesel Lung Urinary bladder Lead compounds, inorganic Stomach Polychlorinated biphenyls Hepatobiliary tract Polychlorophenols or their sodium salts (combined exposures) Non

- Hodgkin lymphoma Soft

- tissue sarcoma Tetrachloroethylene Cervix Non

- Hodgkin Lymphoma E sophagus Trichloroethylene Liver and biliary tract Non

- Hodgkin Lymphoma



### Table 3. WTC

- related health conditions specified in the Zadroga Act that may be associated with cancer through chronic inflammation or irritation
Upper airway

 Chronic rhinos inusitis

 Chronic nasopharyngitis

 Chronic laryngitis

 Chronic airway hyperreactivity

 Cough

 Sleep apnea Lower airway

 Asthma

 Chronic reactive airway dysfunction syndrome

 Chronic obstructive pulmonary disease

 Other chronic respiratory disorder due to fumes and vapors

 Interstitial lung disease Gastrointestinal

 Gastroesophageal reflux41



### Table 4 . Summary of evidence regarding potential carcinogenicity of WTC exposures by cancer site
Cancer site Carcinogenic agents at WTC with sufficient or limit ed evidence in humans 100 

### WTC
- related Conditions FDNY Study

Cancers with Elevated Standardized Incidence Ratios (SIR’s) 1 

### . **Statistically

significant effects Lip, Oral Cavity, and Pharynx Lip Oral cavity Salivary gland Tonsil Phar ynx Limited: Asbestos (all forms) Chronic nasopharyngitis Nasopharynx Sufficient: Formaldehyde Chronic nasopharyngitis Digestive Organs E sophagus Limited: Tetrachloroethylene GERD Stomach Limited: Asbestos (all forms) Limited: Lead compounds , inorganic GERD Stomach (including gastro
- esophageal junction) Observed Expected SIR (95% CI) Exposed 8 4 2.24 (0.98

– 5.25)** Non

- exposed < 5 2 1.23 (0.40

– 3.83) SIR ratio* 1.82 (0.44

– 7.49 Colon and rectum Limited: Asbestos (all forms) Colon (excluding rectum) Observed Expected SIR (95% CI) Exposed 21 14 1.52 (0.99

– 2.33 Non

- exposed 9 9 1.01 (0.53

– 1.94) SIR ratio* 1.50 (0.69

– 3.27) Anus Liver and bile duct Sufficient: Vinyl chloride Limited: Arsenic and inorganic arsenic compounds Limited: Polychlorinated biphenyls Limited: Trichloroethylene
Gall bladder Pancreas Digestive tract, unspecified Respiratory Organs42

Nasal cavity and paranasal sinus Sufficient: Nickel compounds Limited: Chromium (VI) compounds Limited: Formaldehyde Chronic nasopharyngitis Upper airway hyperreactivity Larynx Sufficient: Acid mists, strong inorganic Sufficient: Asbestos (all forms) Chronic laryngitis

Lung Sufficient: Arsenic and inorganic arsenic compounds Sufficient: Asbestos (all forms) Sufficient: Beryllium and beryllium compounds Sufficient: Cadmium and cadmium compounds Sufficient: Chromium(VI) compounds Sufficient: Nickel compounds Sufficient: Silica dust, crystalline Sufficient: Soot Limited: Acid mis ts, strong inorganic Limited: Engine exhaust, diesel Limited: 2,3,7,8

- Tetrachlorodibenzo

- para dioxin Limited: Welding fumes Interstitial lung disease Chronic respiratory disorder

– fumes/vapors Reactive airways disease syndrome (RADS) Chronic cough syndrom e

Bone, skin, and mesothelial and soft tissue Bone Skin (melanoma) Melanoma Observed Expected SIR (95% CI) Exposed 33 21 1.54 (1.08

– 2.18)** Non

- exposed 1 5 16 0.95 (0.57

– 1.58) SIR ratio* 1.61 (0.87

– 2.9943

Skin (other mali gnant neoplasms) Sufficient: Arsenic and inorganic arsenic compounds Sufficient: Soot Mesothelioma (pleura and peritoneum) Sufficient: Asbestos (all forms) Kaposi sarcoma Soft tissue Limited: Polychlorophenols or their sodium salts (combi ned exposures) Limited: 2,3,7,8

- Tetrachlorodibenzo

- para dioxin Breast and Female Genital Organs Breast Vulva Vagina Uterine cervix Linited: Tetrachloroethylene Endometrium Ovary Sufficient: Asbestos (all forms)
Male G enital Organs Penis Prostate Limited: Arsenic and inorganic arsenic compounds Limited: Cadmium and cadmium compounds Observed Expected SIR (95%CI) Prostate Exposed 90 60 1.49 (1.20

– 1.85)** Non

exposed 45 33 1.35 (1.01

– 1.81)**
SIR r atio* 1.11 (0.77

– 1.59) Prostate, corrected (diagnosis date lagged 2 years) Exposed 73 60 1.21 (0.96

– 1.52) Non

exposed 45 33 1.35 (1.01

– 1.81)**
SIR ratio* 0.90 (0.62

– 1.30) Testis Urinary Tract Kidney Limited: Arsenic and inorganic arse nic compounds Limited: Cadmium and cadmium compounds Renal pelvis and ureter44

Urinary bladder Sufficient: Arsenic and inorganic arsenic compounds Limited: Engine exhaust, diesel Limited: Soot Eye, Brain, and Central Nervous System Eye Sufficient : Welding Extensive f oreign body washout required Brain and central nervous system Endocrine Glands Thyroid Observed Expected SIR (95%CI) Thyroid Exposed 17 6 3.07 (1.86

- 5.08)** Unexposed ≤5 3 0.59 (0.15

– 2.36) SIR ratio* 5.21 (1.19

– 22.74)** Thyroid, corrected (diagnosis date lagged 2 years) Exposed 12 6 2.17 (1.23

– 3.82)** Unexposed ≤5 3 0.59 (0.15

– 2.36) SIR ratio* 3.67 (0.82

– 16.42) Lymphoid, Hematopoietic, and Related T issue Leukemia and/or lymphoma and multiple myeloma* Sufficient: Benzene Sufficient: 1,3

- Butadiene Sufficient: Formaldehyde Limited: Polychlorophenols or their sodium salts (combined exposures) Limited: Styrene Limited: 2,3,7,8

- Tetrachlorodibenzo

- para dio xin Sarcoidosis Observed Expected SIR (95% CI) Non
- Hodgkin lymphoma Exposed 21 13 1.58 (1.03

– 2.42)** Non

- exposed 9 11 0.83 (0.43

– 1.60) SIR ratio* 1.90 (0.87

– 4.15) NHL, corrected ( diagnosis date lagged 2 years) Exposed 20 13 1.50 (0 .97

– 2.33) Non

- exposed 9 11 0.83 (0.43

– 1.60) SIR ratio* 1.81 (0.82

– 3.97) Multiple sites (unspecified) All cancers combined Sufficient: 2,3,7,8

- Tetrachlorodibenzo

para - dioxin *Studies of associations between occupational and environmental ca rcinogens have been complicated by i naccuracies of death certificate diagnosis and changes in classification of cancers of the lymphatic and hematopoietic system (LHC’s) over time. Epidemiologic and animal studies may report morphologically distinct hemato logical cancers as separate endpoints even though they may share common cellular origins. Over time, there has been growing recognition of close relationships and overlap of such morphologically diverse disorders as chronic lymphocytic leukemia and multipl e myeloma, now considered sub classifications of mature B

- cell neoplasms (Swerdlow et al. 2008). For this reason, LHC’s are considered as a combined category in this table.45

Table 5. WTC Human Carcinogens with established mechanistic events for tumor site s (or types) for which there is sufficient evidence in humans (adapted from IARC Monograph Working Group, 2009)

WTC Human Carcinogen Tumor sites (or

types) for which there is sufficient evidence in humans Other sites

with
limited evidence
in humans E stablished mechanistic events

Arsenic and Inorganic arsenic compounds Lung, skin, urinary

bladder Kidney, liver,

prostate Oxidative DNA damage, genomic

instability, aneuploidy, gene amplication, epigenetic effects, DNA

repair inhibition leading to mutag enesis

Asbestos (chrysotile, crocidolite, amosite, tremolite, actinolite, and anthophyllite) Lung,

mesothelioma, larynx, ovary Colorectum,

pharynx, stomach Impaired fiber clearance leading to

macrophage activation, inflammation, generation of reactive oxy gen and nitrogen species, tissue injury, genotoxicity, aneuploidy and polyploidy, epigenetic alteration, activation of signaling pathways, resistance to apoptosis Beryllium and beryllium compounds Lung

-- Chromosome aberrations, aneuploidy, DNA damage

C admium and Cadmium compounds Lung Prostate, kidney DNA

- repair inhibition, disturbance of

tumor

- suppressor proteins leading to genomic stability Chromium (VI) compounds Lung Nasal cavity and paranasal sinuses Direct DNA damage after

intracellular reduction to Cr(III), mutation, genomic instability, aneuploidy, cell transformation Nickel compounds Lung, nasal cavity,

and paranasal -- DNA damage, chromosome aberrations, genomic instability, micronuclei, DNA

- repair inhibition,46 sinuses alteration of DNA methyl ation, histone modification
Silica dust, crystalline in the form of quartz or crystobalite Lung

-- Impaired particle clearance leading to macrophage activation and persistent inflammation47

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