US EPA Integrated Science Assessment for Lead

(June 2013) Statements about Cancer

Collated by Elizabeth O’Brien, Lead Scientist and Lead Advisor, The LEAD Group Inc, Australia, Nov 2021

From the Reference:

United States Environment Protection Agency (US EPA) Integrated Science Assessment for Lead -

[published June 26, 2013, with Errata Sheet Created May 12, 2014],

https://cfpub.epa.gov/ncea/isa/recordisplay.cfm?deid=255721

PREAMBLE - EPA Framework for Causal Determination: Evaluating

Evidence for Inferring Causation page lii [page 54/1886 in whole pdf]

Many of the health and environmental outcomes reported in these studies have complex etiologies.

Diseases such as asthma, coronary heart disease (CHD) or cancer are typically initiated by

multiple agents.

PREAMBLE – Quantitative Relationships: Effects on Human

Populations page lxiii-lxiv [pages 65-66/1886]

…the available human data at ambient concentrations for some environmental pollutants [cont’d next

page] (e.g., particulate matter [PM], O

, lead [Pb], environmental tobacco smoke [ETS], radiation) do

not exhibit thresholds for cancer or noncancer health effects, even though likely mechanisms include

nonlinear processes for some key events.

EXECUTIVE SUMMARY – Health Effects of Pb page lxxxvii [page 89/1886]

Table ES-1 (Continued): Summary

of causal determinations for the

relationship between exposure to

Pb and health effects. lxxxvii Health

Outcome

Causality Determination

(Table with Key Evidence)

Cancer (Section 1.6.7)

Cancer Likely Causal Relationship (Table 4-50)

The animal toxicological literature provides the strong evidence for long-term exposure (i.e., 18 months or 2

years) to high concentrations of Pb (> 2,600 ppm) inducing tumor development; findings from

epidemiologic studies inconsistent. Plausible MOAs are demonstrated.

CHAPTER 1 - INTEGRATIVE SUMMARY – 1.6 Health Effects page 1-19 [page

117/1886]

Table 1-2 (Continued): Summary of causal determinations for the relationship

between exposure to Pb and health effects.

Cancer (Section 4.10.5)

Cancer Likely Causal Relationship (Table 4-50)

The animal toxicological literature provides the strong evidence for long-term exposure (i.e., 18 months or 2 years) to high

concentrations of Pb (> 2,600 ppm) inducing tumor development; findings from epidemiologic studies inconsistent.

Plausible MOAs are demonstrated.

CHAPTER 1 - INTEGRATIVE SUMMARY – 1.6 Health Effects: 1.6.7 Cancer

pages 1-37 – 1-38 [page 135-136/1886]

The toxicological literature provides the strong evidence for the effect of long-term exposure (i.e., 18

months or 2 years) to high concentrations of Pb (> 2,600 ppm) on cancer. The consistent evidence

indicating Pb-induced carcinogenicity in animal models is substantiated by the mode of action

findings from multiple high-quality toxicological [cont’d next page] studies in animal and in vitro

models from different laboratories. Based on such evidence, IARC has classified inorganic Pb

compounds as a probable human carcinogen and the National Toxicology Program has listed Pb and

Pb compounds as “reasonably anticipated to be human carcinogens.” Strong evidence from animal

toxicological studies demonstrates an association between Pb and cancer, genotoxicity or epigenetic

modification. Carcinogenicity in animal toxicology studies with relevant routes of Pb exposure has

been reported in the kidneys, testes, brain, adrenals, prostate, pituitary, and mammary gland, albeit at

high doses of Pb. Epidemiologic studies of cancer incidence and mortality reported inconsistent

results; one strong epidemiologic study demonstrated an association between blood Pb and increased

cancer mortality, but the other studies reported weak or no associations. In the 2006 Pb AQCD,

various indicators of Pb exposure were found to be associated with stomach cancer, and a recent study

on stomach cancer and occupational Pb exposure reported mixed findings depending on the type of Pb

exposure (organic Pb, inorganic Pb, or Pb from gasoline emissions). Similarly, some studies in the

2006 Pb AQCD reported associations between Pb exposure indicators and lung cancer. Recent

epidemiologic studies of lung cancer focused on occupational exposures and reported inconsistent

associations. The majority of epidemiologic studies of brain cancer had null results overall, but

positive associations between Pb exposure indicators and brain cancer were observed among

individuals with certain genotypes. Overall, the consistent and strong body of evidence from

toxicological studies on carcinogenicity and potential modes of action but inconsistent epidemiologic

evidence is sufficient to conclude that a causal relationship is likely to exist between Pb exposure and

cancer.

CHAPTER 1 - INTEGRATIVE SUMMARY – 1.8 Integration of Health and

Ecological Effects page 1-61 [page 159/1886]

Table 1-4 Summary of causal determinations for health and ecological effects.

Outcome/Effect Human Health

Causal

Determinationa

Ecological Receptors

Causal

Determinationa

…

Cancer Likely to be a causal

relationship

N/A

CHAPTER 1 - INTEGRATIVE SUMMARY – 1.8.1 Modes of Action Relevant to

Downstream Health and Ecological Effects page 1-64 [page 162/1886]

Table 1-5 Modes of action, their related health effects, and information on

concentrations eliciting the MOAs.

Mode of Action

[Related Health Effects (ISA Section)]

Concentrations or Doses (Conditions)

…

Blood Pb Dose

Cell Death/Genotoxicity

[Cancer (4.10), Reproductive and

Developmental Effects (4.8), Bone

and Teeth (4.9.4)]

3.3 μg/dL

(Concurrent median in adult

women; increased rate of

hypoxanthine guanine phospho

ribosyltransferase reporter gene

[HPRT] mutation frequency)

Van et al. (2004)

0.03 μM Pb acetate

(In vitro; 18 hours; increased

formation of micronuclei)

Bonacker et al. (2005)

This table provides examples of studies that report effects with low doses or concentration; they are

not the full body of evidence used to characterize the weight of the evidence. In addition, the levels

cited are reflective of the data and methods available and do not imply that these modes of action are

not acting at lower Pb exposure or blood Pb levels or that these doses represent the threshold of the

effect. Additionally, the blood concentrations and doses (indicating Pb exposure concentrations from

in vitro systems) refer to the concentrations and doses at which these modes of action were observed.

While the individual modes of action are related back to specific health effects sections (e.g., Nervous

System, Cardiovascular), the concentrations and doses given should not be interpreted as levels at

which those specific health effects occur.

CHAPTER 1 - INTEGRATIVE SUMMARY – 1.10 Summary page 1-90 [page 188/1886]

Table 1-8 (Continued): Summary of evidence from epidemiologic, animal

toxicological and ecological studies on the effects associated with exposure to Pb.

Endpoint Evidence in the 2006 Pb

AQCD

Evidence in the 2013 Pb ISA

Cancer

Cancer Epidemiologic studies of highly

exposed occupational populations

suggest a relationship between Pb

and cancers of the lung and the

stomach; however the evidence is

limited by the presence of various

potential confounders, including

metal co-exposures (e.g., to As, Cd),

smoking, and dietary habits. The

2003 NTP and 2004 IARC reviews

concluded that Pb and Pb

compounds were probable

carcinogens, based on limited

evidence in humans and sufficient

evidence in animals. Based on

animal data and inadequate human

data Pb and Pb compounds would

be classified as likely carcinogens

according to the EPA Cancer

Assessment Guidelines for

Carcinogen Risk Assessment.

The toxicological literature

continues to provide the strongest

evidence for Pb exposure and cancer

with supporting evidence provided

by the epidemiologic literature.

Epidemiologic studies of cancer

incidence and mortality reported

inconsistent results.

CHAPTER 1 - INTEGRATIVE SUMMARY – References for Chapter 1 page 1-101 [page

199/1886]

Weisskopf, MG; Jain, N; Nie, HL; Sparrow, D; Vokonas, P; Schwartz, J; Hu, H. (2009). A prospective study of

bone lead concentration and death from all causes, cardiovascular diseases, and cancer in the department of

veterans affairs normative aging study. Circulation 120: 1056-1064.

http://dx.doi.org/10.1161/circulationaha.108.827121

CHAPTER 3 - EXPOSURE, TOXICOKINETICS, AND BIOMARKERS – 3.3 Pb

Biomarkers page 3-55 [page 518/1886]

Numerous mechanistic models of Pb biokinetics in humans have been proposed, and these are

described in the 2006 Pb AQCD (U.S. EPA, 2006b) and in the supporting literature cited in that

report. In this section, for simplicity and for internal consistency, discussion is limited to predictions

from a single model, the ICRP Pb biokinetics model (Pounds and Leggett, 1998; ICRP, 1994; Leggett,

1993). The ICRP model consists of a systemic biokinetics model (Leggett, 1993) and a human

respiratory tract model (ICRP, 1994). The Leggett model simulates age-dependent kinetics of tissue

distribution and excretion of Pb ingestion and inhalation intakes. This model was originally developed

for the purpose of supporting radiation dosimetry predictions and it has been used to develop cancer

risk coefficients for internal radiation exposures to Pb and other alkaline earth elements that have

biokinetics similar to those of calcium (ICRP, 1993).

CHAPTER 3 - EXPOSURE, TOXICOKINETICS, AND BIOMARKERS – References for

Chapter 3 page 3-179 [page 642/1886]

Weisskopf, MG; Jain, N; Nie, HL; Sparrow, D; Vokonas, P; Schwartz, J; Hu, H. (2009). A prospective study of

bone lead concentration and death from all causes, cardiovascular diseases, and cancer in the department of

veterans affairs normative aging study. Circulation 120: 1056-1064.

http://dx.doi.org/10.1161/circulationaha.108.827121

CHAPTER 4 - INTEGRATED HEALTH EFFECTS OF LEAD EXPOSURE – 4.1

Introduction page 4-1 [page 645/1886]

Chapter 4 concludes with a discussion of the evidence for the cancer effects of Pb (Section 4.10).

CHAPTER 4 - INTEGRATED HEALTH EFFECTS OF LEAD EXPOSURE – 4.2.8

Summary page 4-52 [page 696/1886]

Table 4-2 MOAs, their related health effects, and information on concentrations

eliciting the MOAs.

Mode of Action

[Related Health Effects (ISA Section )]

Concentrations or Doses (Conditions)

… Blood Pb Dose

Cell Death/Genotoxicity

[Cancer (4.10), Reproductive and

Developmental Effects (4.8), Bone

and Teeth (4.9.4)]

3.3 μg/dL

(Concurrent median in adult

women; increased rate of HPRT

mutation frequency)

Van Larebeke et al. (2004)

0.03 μM Pb acetate

(In vitro; 18 hours; increased

formation of micronuclei)

Bonacker et al. (2005)

This table provides examples of studies that report effects with low Pb dosages or concentrations; they are not

the full body of evidence used to characterize the weight of the evidence. In addition, the levels cited are

reflective of the data and methods available and do not imply that these modes of action are not acting at lower

Pb exposure or blood Pb levels or that these doses represent the threshold of the effect. Additionally, the blood

concentrations and doses (indicating Pb concentrations from in vitro systems) refer to the concentrations and

doses at which these modes of action were observed. While the individual modes of action are related back to

specific health effects sections (e.g., Nervous System, Cardiovascular), the concentrations and doses given

should not be interpreted as levels at which those specific health effects occur. Also, the data presented in this

table do not inform the exposure frequency and duration required to elicit a particular MOA.

CHAPTER 4 - INTEGRATED HEALTH EFFECTS OF LEAD EXPOSURE – 4.4.5

Mortality page 4-389 [page 1033/1886]

Using NHANES II (1976-1980) data, Lustberg and Silbergeld (2002) found significant increases in all-

cause mortality, circulatory mortality, and cancer mortality, comparing adults with blood Pb levels of

20-29 μg/dL to those with blood Pb levels less than 10 μg/dL (measured 12-16 years before

ascertainment of vital status). Using NHANES III data, Schober et al. (2006) found significant

increased all-cause, cardiovascular, and cancer mortality comparing adults with blood Pb levels from

5-9 μg/dL and above 10 μg/dL to those with blood Pb levels less than 5 μg/dL (measured a median of

8.8 years before ascertainment of vital status).