Business interests like oil and coal, eager to see reduced regulation, were quick to hail Wheeler's confirmation while Democrats and conservation groups are anxious that environmental rollbacks under the Trump administration are going too far.
"The policies he has supported as acting administrator are not in the best interest of our environment and public health, particularly given the threat of climate change to our nation", she said.
Wheeler, who graduated from Fairfield High School in 1983, has been acting administrator since July, when former EPA Administrator Scott Pruitt resigned amid a host of ethics controversies.
"Throughout his career, Andrew Wheeler has shown a clear disregard for the EPA's mission to protect the public and environment", said Democratic Senator Dianne Feinstein from California, after voting against him.
"With Andrew Wheeler-dealer at the helm, it's truly time to rename EPA the 'Environmental Pollution Agency, '" declared Martin Hayden, vice president of policy and legislation Earthjustice.
"Time and time again Mr. Wheeler has proven that his environmental policies are nearly as destructive and extreme has his predecessors'", he said.
But most Republicans, including Senate Environment and Public Works Committee Chairman John Barrasso of Wyoming, said Wheeler had eased the burden on industry without undermining key environmental protections.
"These efforts are of great importance to the state of ME, which is located at the end of our nation's "air pollution tailpipe" and is on the receiving end of pollution generated by coal-fired power plants in other states", she said.
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Democrats used the vote as an opportunity to call for greater action on climate change, with more than six senators speaking to a almost empty chamber about why the federal government should press for steeper cuts in greenhouse gas emissions.
And Renewable Fuels Association (RFA) President and CEO Geoff Cooper added, "We congratulate Administrator Wheeler on his Senate confirmation".
The planet has already warmed more than 1 degree C (1.8 degrees F) above pre-industrial levels. "With each rollback, Wheeler is stacking the deck in favor of the polluting corporations who formerly employed him, leaving our families to pay the price of more toxic pollution with their health".
In response, Wheeler, despite admitting he hadn't read the multiagency report, dismissed its findings and threatened to intervene in the drafting of the next National Climate Assessment.
Wheeler's nomination has been welcomed by businesses eager to see reduced regulation, but upset Democrats and conservation groups anxious that environmental rollbacks under the Trump administration are going too far. He proposed loosening requirements that coal-fired power plants reduce carbon dioxide emissions.
While Democrats initially viewed Wheeler as a pragmatic technocrat with whom they could forge a handful of policy compromises, they expressed disappointment over key decisions he has made at the agency.
Environmental groups reacted to Thursday's confirmation much as they did when Wheeler took the reins as deputy administrator.