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THE FOG OF WAR  
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Dennis Normile
April 24, 2025
Science
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_ Fifty years after the Vietnam War, researchers are still struggling
to document the long-term health effects of the massive spraying of
Agent Orange and other herbicides _

During the war in Vietnam, the U.S. military sprayed herbicides on an
estimated 2.2 million hectares of forest and farmland., HORST FAAS/AP

 

Nearly 2 decades ago, more than 240 women who had recently given birth
in Da Nang, Vietnam, got an unusual request from visiting nurses
checking on their newborns: Could we collect a small sample of your
breast milk?

The mothers had volunteered for a study scientists hoped would answer
a question that had haunted Vietnam since what it calls the Resistance
War Against America ended in 1975: Had the U.S. military’s massive
aerial spraying of vegetation-killing chemicals during the conflict
put children’s health at risk?

By the time the milk-collecting effort began in 2008, researchers
already knew those herbicides—collectively called Agent Orange,
after the orange stripe painted on the barrels holding one
formulation—were tainted with a highly toxic dioxin, a long-lived
chemical linked to an array of human health problems. Postwar surveys
had found that relatively high concentrations of dioxin lingered in
some of Vietnam’s soils and aquatic sediments, especially near
former U.S. air bases—such as the one in Da Nang—that had handled
vast volumes of the chemicals. And Agent Orange had been anecdotally
linked to reports of birth defects in communities exposed to the
spraying, which lasted from 1961 to 1971.

Vast swaths of forest and farmland in South Vietnam were denuded by
the U.S. military's spraying of herbicides from 1961 to 1971. Archive
Image/Alamy

As years went by, Vietnam asserted that those harmed by Agent Orange
included the second-, third-, and even fourth-generation relatives of
those who experienced the spraying, because of dioxin lingering in the
environment or inherited health effects. The country put birth defects
at the center of its descriptions of the horrors of Agent Orange. But
few studies had attempted to rigorously examine a link, until the Da
Nang work. Led by environmental health scientist Muneko Nishijo of
Kanazawa Medical University and public health specialist Tai Pham-The
of the Vietnam Military Medical University, it aimed to document
dioxin levels in the milk of new mothers, then follow their children
as they matured.
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Now, Vietnam is preparing to mark the 50th anniversary of the event
that ended the war—the capture of Saigon, now Ho Chi Minh City, by
North Vietnamese and Viet Cong forces on 30 April 1975. Yet that study
remains one of the few ongoing research efforts on the long-term
health effects of the bitter conflict, which cost the lives of some
3.3 million Vietnamese and nearly 60,000 U.S. service members. It did
not resolve the birth defects question. But Nishijo and Tai did find
evidence that the chemical can affect brain development in exposed
children, and others are studying how the conflict is still affecting
the physical and mental health of those who lived through it (see
sidebar, below
[[link removed]]).

By now, most Vietnamese have no memory of the war, as the majority of
the nation’s 101 million people were born after it ended. And
finding support for studies to understand the war’s continuing
impact is proving increasingly difficult, as neither the United States
nor Vietnam appears eager to revisit that era. But, “The ongoing
burden of disease among exposed populations means that Vietnam’s
dioxin legacy remains a significant public health challenge,” says
environmental health scientist Tran Thi Tuyet-Hanh of the Hanoi
University of Public Health.

The Vietnam War marked the biggest deployment of herbicidal warfare
the world has ever seen. Between 1961 and 1971, lumbering aircraft
sprayed an estimated 74 million liters of the chemicals over South
Vietnam as well as border areas of Laos and Cambodia. The goal was to
strip foliage from mangrove swamps and dense forests that were
providing cover for North Vietnamese and Viet Cong troops, and to
destroy crops they relied on for food.

The weapons of choice were called the rainbow herbicides—a
half-dozen formulations identified by names such as Agent Pink and
Agent White, after the colors used to mark barrels. Agent Orange,
which became the most notorious, was a 50-50 blend of two commercially
available herbicides, 2,4-dichlorophenoxyacetic acid and
2,4,5-trichlorophenoxyacetic acid (2,4,5-T). The defoliants were
believed to be harmless to humans, and U.S. troops typically handled
them without wearing protective gear.

By the late 1960s, however, lab experiments showed 2,4,5-T could cause
abnormalities and stillbirths in mice, and there were reports of human
birth defects in sprayed areas of Vietnam. Later it became clear that
the herbicide manufacturing process introduced a particularly toxic
dioxin, known as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), into
Agent Orange and other herbicides. Four years before the war ended,
the U.S. abandoned its decadelong spraying campaign amid mounting
international condemnation and concerns about safety.

Today, there is broad consensus that dioxin poses serious health risks
to those directly exposed, including Vietnamese citizens and soldiers
as well as members of the armed forces of the U.S. and other countries
that aided it during the war: South Korea, Australia, and New Zealand.
That consensus rests, in part, on efforts by the U.S. government to
assess how exposure affected the health of U.S. veterans. In 1992, the
Department of Veterans Affairs asked the Institute of Medicine, now
part of the U.S. National Academies of Sciences, Engineering, and
Medicine (NASEM), to review the scientific literature and provide
biennial updates. The last of those reports, _Veterans and Agent
Orange, [[link removed]]_ appeared in 2018
and identified 19 cancers and other conditions with “sufficient”
or “suggestive” evidence of an association with exposure to the
herbicides (see box, above
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Vietnamese investigators separately produced a similar list.

But such studies largely left open one of the most visible and
contentious questions surrounding Agent Orange: whether the compounds
pose risks not just for those who were directly exposed, but for their
children.

The concern about future generations was prompted, in large part, by
the worrisome staying power of TCDD, the dioxin that contaminated
Agent Orange. Unlike the herbicide itself, which decomposes within
hours to days, TCDD can survive up to 3 years in soil that is exposed
to sunlight. If leached into river or pond sediment, it can have a
half-life of more than 100 years—more than enough time to be picked
up by fish, ducks, and other animals that people eat. (People can also
inhale contaminated dust and absorb dioxin through the skin.) Once in
the human body, dioxin can lodge in breast and other fatty tissue and
have a half-life of 7 to 11 years. It can also contaminate breast milk
and be passed to breastfeeding babies.

Since the 1970s, numerous animal studies have found that fetuses
exposed to dioxin can exhibit a wide range of birth defects and
developmental problems, suggesting an impact on human fetuses is
biologically plausible. But documenting it has proved difficult.

Because of the Agent Orange spraying, Vietnam was the obvious place to
seek an answer. In 2003, the U.S. National Institute of Environmental
Health Sciences (NIEHS) approved a 5-year, $3.5 million study proposed
by public health physician David Carpenter of the University at
Albany. It planned to analyze dioxin levels in the blood of 300
Vietnamese mothers of babies with birth defects, using 300 mothers of
healthy infants as controls. But NIEHS canceled the study in 2005
after failing to agree on research protocols with Vietnam’s Ministry
of Health.

The next year, a team led by Tuan Van Nguyen, then at the Garvan
Institute of Medical Research, published a meta-analysis of 22
studies, including unpublished Vietnamese-language reports, that
suggested mothers exposed to Agent Orange were twice as likely to
have children with birth defects as those not exposed.
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that conclusion, reported in the _International Journal of
Epidemiology_, proved controversial. In a commentary in the same
journal, toxicologist Arnold Schecter of the University of Texas and
surgeon John Constable of Harvard Medical School criticized the paper
for relying on old, non–peer-reviewed publications. “We know of no
non-Vietnamese studies linking herbicide or dioxin exposure to
congenital malformations other than spina bifida and anencephaly,
[[link removed]]”
the pair wrote. (In 2014, the NASEM committee that produced that
year’s update to _Veterans and Agent Orange_ reviewed additional
evidence and concluded it was “inadequate or insufficient” to link
Agent Orange to any birth defects, including spina bifida.)

In Vietnam, the government has asserted that contamination from
herbicide spraying by the U.S. military is responsible for birth
defects. Paula Bronstein/Getty Images

Nguyen, now at the University of Technology Sydney, says that although
their work suggested an association between Agent Orange exposure and
birth defects, many of the studies they drew on were observational. As
a result, “We avoided causal conclusions.” But more rigorous
cohort studies that tracked individuals in a way that would rule out
confounding factors, such as maternal age and exposure to other
chemicals, could yield firmer conclusions, he says.

A good opportunity to launch those studies was missed, Nguyen says. By
the mid-2000s, Vietnamese and U.S. researchers had measured the dioxin
burdens of a significant number of individuals from across Vietnam,
which could have enabled a large-scale study of the birth defects
question. But Vietnamese authorities never acted on Nguyen’s
suggestion to use those data. “The study was entirely feasible, yet
it was never conducted, which was deeply disappointing,” Nguyen
says.

Several factors explain the lackluster support, scientists say. One is
that the topic “is extremely political” in both Vietnam and the
U.S., Carpenter says. For example, if his 2003 study “had shown what
we expected”—that herbicide exposure was linked to birth
defects—the U.S. might have been “expected to pay reparations to
Vietnamese children.” Alternatively, if it had found no link, that
might have “embarrassed” the Vietnamese government, which has long
highlighted birth defects as Agent Orange’s most prominent harm.

At this point, Carpenter says, “It looks increasingly hopeless to
think that an adequate study [of the birth defects question] will ever
be funded and done.”

For the moment, Nishijo’s and Tai’s breast milk study is the only
ongoing epidemiological study focusing on dioxin in Vietnam, Nishijo
notes. Launched in Da Nang, it has since expanded to a second cohort
near the former Bien Hoa Air Base, another hot spot, and a control
group. But the study is unlikely to provide a definitive answer to the
birth defects question. “Our cohort is too small to investigate
congenital anomalies,” because they occur rarely, Nishijo says.

Still, in dozens of papers published over the past 15 years,
[[link removed]] the team has documented
other links. In particular, they have found that a high level of
dioxin in a mother’s milk—a proxy for fetal exposure—is
associated with slower physical growth and lagging neurodevelopment in
their children. Boys exhibit learning difficulties, for example,
whereas girls show attention deficit hyperactivity disorder and
autism.

The papers “provide strong evidence” that living near sites
contaminated by Agent Orange can result in high dioxin body burdens
that are associated with behavioral disorders in children, says Steven
Stellman, an epidemiologist now retired from Columbia University who
was long involved in Agent Orange studies.

If funding allows, Nishijo and Tai intend to keep following the
children as they age. That could reveal links between dioxin exposure
and cancers and other diseases that manifest later in life.

In the meantime, other researchers say there’s another issue
surrounding the long-term health impacts of Agent Orange that could
still be studied—if funders are willing to step forward. It is the
question of whether exposure has caused fundamental biological changes
in people that can be handed down from generation to generation.

Vietnamese scientists and officials contend they are seeing such
multigenerational effects resulting in birth defects several
generations after exposure. And although the authors of the 2018 NASEM
report concluded there was “inadequate or insufficient evidence”
of epigenetic effects, they strongly encouraged more study of the
issue.

The deformed hand of Nguyen Van Danh, whose father and grandparents
lived in areas sprayed with herbicides during the Vietnam War.
Establishing direct links between herbicide exposure and birth defects
has proved difficult. Kuni Takahashi/Getty Images

Here, too, there is suggestive evidence from animal experiments.
Michael Skinner, a biologist at Washington State University, has
reported that, in rodents, genetic changes and adult-onset diseases
linked to dioxin exposure can be seen in fourth-generation
descendants.

Recent human research also lends support to the idea. Cristina
Giuliani, a biological anthropologist at University of Bologna, and
colleagues at the Hue University of Medicine and Pharmacy and the
University of California (UC), Riverside focused on an epigenetic
mechanism called DNA methylation and how it affected the expression of
one particular gene, _CYP1A1_, which has a role in breaking down
toxic compounds, making them easier to be eliminated from the body.
“TCDD is different as it cannot be fully detoxified and its presence
further stresses the detoxification system,” she says. In a
2018 _Environmental Pollution_ paper, they reported that the
offspring of Vietnamese parents exposed to Agent Orange shared a
distinctive _CYP1A1_ DNA methylation signature
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was not seen in the children of parents with no exposure.

Giuliani is careful to note that the study “does not experimentally
demonstrate that exposure to dioxin is transmitted to descendants.”
And it does not address the question of whether any changes are
harmful, beneficial, or neutral.

Getting a firmer grip on those issues, researchers say, would require
epigenetic studies comparing several generations of exposed and
nonexposed populations. But there are “no studies like that yet,”
Skinner says. And finding the funding to conduct such studies in
Vietnam, he says, “would be difficult … due to the politics of the
situation.”

The 50th anniversary of the end of the war is likely to draw renewed
attention to the Agent Orange era. But many researchers doubt it will
lead to a substantial surge in scientific activity. One obstacle is
that Vietnam now has “more pressing environmental health issues,”
such as increasingly severe air pollution from sources including the
widespread burning of plastic waste, says David Biggs, an
environmental historian at UC Riverside who has studied the Agent
Orange controversy.

Another hurdle is that the impact of Agent Orange is fading. In the
early 2000s, the Vietnam Red Cross Society estimated 3 million people
were affected by the spraying and lingering contamination. But those
who were directly exposed to the spray are dying, and ongoing exposure
“will become less and less because this dioxin no longer exists in
the environment” as it breaks down, says Le Ke Son, a toxicologist
who led the Vietnamese government’s efforts to deal with the
herbicides. The U.S. has also paid to clean up some contaminated
sites, although one or two hot spots still persist. (President Donald
Trump’s administration suspended but later restored funding for a
cleanup of the Bien Hoa site.) And even if biological changes due to
exposure can be inherited, “those born with severe disabilities are
less likely to marry and have children,” says Charles Bailey, who
spearheaded the Ford Foundation’s efforts to address Agent Orange
issues in Vietnam in the early 2000s.

Still, even 50 years on, Agent Orange casts a dark shadow over
Vietnam. And Carpenter, for one, believes “we are missing a very
important opportunity to understand more about the risks.”

With reporting by Le My in Ho Chi Minh City, Vietnam.

doi: 10.1126/science.zzbnow6

_DENNIS NORMILE writes about research and science policy developments
in Asia, particularly China and Japan. He is based in Tokyo._

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* Science
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* Vietnam War
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* Agent Orange
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* genetics
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* cancer
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* birth defects
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* dioxin
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* herbicides
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